MODEL9089491423
type: SBMLModel
species: 400558
curated: false
reaction: 407957
reaction: 405017
name: Ajay_Bhalla_2004_PKM_Tuning
species: 403457
reaction: 405297
species: 401117
reaction: 408397
reaction: 406777
reaction: 404577
reaction: 404857
rule: 404417
reaction: 407037
species: 403577
reaction: 406857
reaction: 408117
species: 403777
reaction: 407217
species: 401777
species: 402377
species: 403017
species: 403977
species: 400917
species: 401137
reaction: 407377
species: 402917
reaction: 407697
reaction: 405397
species: 400817
reaction: 405557
species: 400637
species: 401617
species: 401037
species: 403137
reaction: 406217
reaction: 405077
species: 402957
time units: 131570
species: 401817
species: 404297
reaction: 405777
reaction: 405377
reaction: 408237
species: 401157
species: 402857
units def: 424842
species: 403997
reaction: 408097
reaction: 408337
species: 401557
species: 402157
reaction: 405937
reaction: 407397
reaction: 404897
species: 400797
reaction: 408057
reaction: 404937
reaction: 407477
reaction: 407077
reaction: 408157
species: 403077
species: 402417
reaction: 407777
reaction: 406277
reaction: 404777
species: 401837
reaction: 405657
species: 404317
reaction: 407457
species: 404077
reaction: 406377
reaction: 406077
reaction: 405157
reaction: 405477
species: 401877
reaction: 405957
reaction: 405677
reaction: 407177

400558
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 3.72077777777778E-17
initial amount: NaN
in compartment: 400538

400538
type: Compartment
constant: true
size: 1.5E-15
spatial dimensions: 3.0

407957
type: Reaction
kinetic law: 433371
product: 433359
reactant: 433347
reactant: 433335
notes: From Seki et al ABB 316(2):673-679
fast: false
reversible: true

433371
type: KineticLaw
local parameters: 569279
local parameters: 569278
notes: k1*CaM_slash_neurogranin_star_*CaM_po_Ca_pc_n_minus_CaNAB-k2*CaM_po_Ca_pc_n_minus_CaNAB_slash_dephosph_neurogranin_slash_dephosph_neurogranin_cplx

569279
type: LocalParameter
units: 424878
value: 4.005E-15

424902
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND

424890
type: SBMLUnit
exponent: 1.0
scale: 0
multipler: 1.0
kind: LITRE

569278
type: LocalParameter
units: 424962
value: 5.004045E-16

424998
type: SBMLUnit
exponent: -1.0
scale: 0
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kind: SECOND

424986
type: SBMLUnit
exponent: -1.0
scale: -6
multipler: 1.0
kind: MOLE

424974
type: SBMLUnit
exponent: 2.0
scale: 0
multipler: 1.0
kind: LITRE

433359
type: SpeciesReference
stoichiometry: 1.0
species: 403037

403037
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

433347
type: SpeciesReference
stoichiometry: 1.0
species: 404357

404357
type: Species
constant: false
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

433335
type: SpeciesReference
stoichiometry: 1.0
species: 402957

402957
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405017
type: Reaction
kinetic law: 426363
product: 426351
reactant: 426339
reactant: 426327
notes: Assume the binding is fast and limited only by the amount of Ras* available. So kf=kb/[craf-1] If kb is 1/sec, then kf = 1/0.2 uM = 1/(0.2 * 6e5) = 8.3e-6 Later: Raise it by 10 X to 4e-5 From Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is complexed with Ras. So we raise kb 4x to 4 This step needed to memb-anchor and activate Raf: Leevers et al Nature 369 411-414 May 16, 2003 Changed Ras and Raf to synaptic levels, an increase of about 2x for each. To maintain the percentage of complexed Raf, reduced the kf by 2.4 fold to 10.
fast: false
reversible: true

426363
type: KineticLaw
local parameters: 568890
local parameters: 568887
notes: kf*MAPK_slash_craf_minus_1_star_*Ras_slash_GTP_minus_Ras-kb*MAPK_slash_Raf_star__minus_GTP_minus_Ras

568890
type: LocalParameter
units: 424878
value: 7.5E-16

568887
type: LocalParameter
units: 424962
value: 1.499985E-14

426351
type: SpeciesReference
stoichiometry: 1.0
species: 401657

401657
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
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426339
type: SpeciesReference
stoichiometry: 1.0
species: 401977

401977
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426327
type: SpeciesReference
stoichiometry: 1.0
species: 401417

401417
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

403457
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405297
type: Reaction
kinetic law: 426958
product: 426946
reactant: 426934
reactant: 426922
notes: Nice curves from Homma et al JBC 263:14 6592-6598 1988 Fig 5c. The activity falls above 10 uM, but that is too high to reach physiologically anyway, so we will ignore the higher pts and match the lower ones only. Half-max at 1 uM. But Wahl et al JBC 267:15 10447-10456 1992 have half-max at 56 nM which is what I\'ll use.
fast: false
reversible: true

426958
type: KineticLaw
local parameters: 568946
local parameters: 568943
notes: kf*PLC_g_slash_PLC_g*Ca-kb*PLC_g_slash_Ca_dot_PLC_g

568946
type: LocalParameter
units: 424878
value: 1.5E-14

568943
type: LocalParameter
units: 424962
value: 2.7E-13

426946
type: SpeciesReference
stoichiometry: 1.0
species: 402557

402557
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426934
type: SpeciesReference
stoichiometry: 1.0
species: 403917

403917
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.08
initial amount: NaN
in compartment: 400538

426922
type: SpeciesReference
stoichiometry: 1.0
species: 402517

402517
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.82
initial amount: NaN
in compartment: 400538

401117
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408397
type: Reaction
kinetic law: 434436
product: 434423
product: 434410
reactant: 434398
fast: false
reversible: false

434436
type: KineticLaw
local parameters: 569330
notes: k3*AC_slash_PDE1_slash_PDE1_slash_PDE1_cplx

569330
type: LocalParameter
units: 424878
value: 2.5005E-15

434423
type: SpeciesReference
stoichiometry: 1.0
species: 403817

403817
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 2.0
initial amount: NaN
in compartment: 400538

434410
type: SpeciesReference
stoichiometry: 1.0
species: 403697

403697
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 325493.333333333
initial amount: NaN
in compartment: 400557

400557
type: Compartment
constant: true
size: 2.5E-21
spatial dimensions: 3.0

434398
type: SpeciesReference
stoichiometry: 1.0
species: 403837

403837
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406777
type: Reaction
kinetic law: 430485
product: 430474
product: 430460
reactant: 430448
fast: false
reversible: false

430485
type: KineticLaw
local parameters: 569160
notes: k3*PP1_minus_active_slash_Deph_minus_thr305_slash_Deph_minus_thr305_cplx

569160
type: LocalParameter
units: 424878
value: 5.25E-16

430474
type: SpeciesReference
stoichiometry: 1.0
species: 402797

402797
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.8
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430460
type: SpeciesReference
stoichiometry: 1.0
species: 402677

402677
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

430448
type: SpeciesReference
stoichiometry: 1.0
species: 402837

402837
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

404577
type: Reaction
kinetic law: 425340
product: 425328
reactant: 425316
reactant: 425304
fast: false
reversible: true

425340
type: KineticLaw
local parameters: 568802
local parameters: 568799
notes: kf*temp_minus_PIP2*PLA2_slash_PLA2_minus_cytosolic-kb*PLA2_slash_PIP2_minus_PLA2_star_

568802
type: LocalParameter
units: 424878
value: 7.5E-16

568799
type: LocalParameter
units: 424962
value: 1.799955E-18

425328
type: SpeciesReference
stoichiometry: 1.0
species: 400817

400817
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

425316
type: SpeciesReference
stoichiometry: 1.0
species: 400757

400757
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.4
initial amount: NaN
in compartment: 400538

425304
type: SpeciesReference
stoichiometry: 1.0
species: 404097

404097
type: Species
notes: This isn\'t explicitly present in the M&L model, but is obviously needed. I assume its conc is fixed at 1uM for now, which is a bit high. PLA2 is stim 7x by PIP2 @ 0.5 uM (Leslie and Channon BBA 1045:261(1990) Leslie and Channon say PIP2 is present at 0.1 - 0.2mol% range in membs, which comes to 50 nM. Ref is Majerus et al Cell 37 pp 701-703 1984 Lets use a lower level of 30 nM, same ref....
constant: true
boundary condition: true
has only substance units: false
initial concentration: 2.5
initial amount: NaN
in compartment: 400538

404857
type: Reaction
kinetic law: 425975
product: 425963
product: 425951
reactant: 425939
notes: kf = kg1 = 0.01/sec, kb = 0. This is the basal exchange of GTP for GDP.
fast: false
reversible: true

425975
type: KineticLaw
local parameters: 568858
local parameters: 568855
notes: kf*Gq_slash_G_minus_GDP-kb*G_star_GTP*BetaGamma

568858
type: LocalParameter
units: 424962
value: 0.0

568855
type: LocalParameter
units: 424878
value: 1.5E-19

425963
type: SpeciesReference
stoichiometry: 1.0
species: 401217

401217
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

425951
type: SpeciesReference
stoichiometry: 1.0
species: 401237

401237
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

425939
type: SpeciesReference
stoichiometry: 1.0
species: 401277

401277
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 400538

407037
type: Reaction
kinetic law: 431126
product: 431114
reactant: 431102
reactant: 431090
notes: See parent PPhosphatase2A for parms
fast: false
reversible: true

569186
type: LocalParameter
units: 424878
value: 3.6E-14

569185
type: LocalParameter
units: 424962
value: 2.87415E-15

431114
type: SpeciesReference
stoichiometry: 1.0
species: 401797

401797
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

431102
type: SpeciesReference
stoichiometry: 1.0
species: 401777

401777
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 400538

431090
type: SpeciesReference
stoichiometry: 1.0
species: 401417

403577
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406857
type: Reaction
kinetic law: 430678
product: 430666
product: 430654
reactant: 430642
fast: false
reversible: false

430678
type: KineticLaw
local parameters: 569169
notes: k3*MAPK_slash_Raf_minus_GTP_minus_Ras_slash_Raf_minus_GTP_minus_Ras_dot_2_slash_Raf_minus_GTP_minus_Ras_dot_2_cplx

569169
type: LocalParameter
units: 424878
value: 4.5E-16

430666
type: SpeciesReference
stoichiometry: 1.0
species: 401597

401597
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

430654
type: SpeciesReference
stoichiometry: 1.0
species: 401517

401517
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

430642
type: SpeciesReference
stoichiometry: 1.0
species: 401637

401637
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408117
type: Reaction
kinetic law: 433757
product: 433745
reactant: 433733
reactant: 433720
notes: k1 changed from 3.3e-6 to 6.6e-6
fast: false
reversible: true

433757
type: KineticLaw
local parameters: 569294
local parameters: 569293
notes: k1*PP1_slash_PP1_minus_I1_star_*PP2A-k2*PP2A_slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__cplx

569294
type: LocalParameter
units: 424878
value: 3.75E-14

569293
type: LocalParameter
units: 424962
value: 5.94E-15

433745
type: SpeciesReference
stoichiometry: 1.0
species: 403217

403217
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

433733
type: SpeciesReference
stoichiometry: 1.0
species: 403177

403177
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.12
initial amount: NaN
in compartment: 400538

433720
type: SpeciesReference
stoichiometry: 1.0
species: 403137

403137
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

403777
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407217
type: Reaction
kinetic law: 431560
product: 431547
product: 431535
reactant: 431523
fast: false
reversible: false

431560
type: KineticLaw
local parameters: 569202
notes: k3*Ras_slash_GEF_minus_Gprot_minus_bg_slash_GEF_minus_bg_act_minus_ras_slash_GEF_minus_bg_act_minus_ras_cplx

569202
type: LocalParameter
units: 424878
value: 3.0E-17

431547
type: SpeciesReference
stoichiometry: 1.0
species: 401877

401877
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

431535
type: SpeciesReference
stoichiometry: 1.0
species: 401977

431523
type: SpeciesReference
stoichiometry: 1.0
species: 401897

401897
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

402377
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

403017
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

403977
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.00555555555555556
initial amount: NaN
in compartment: 400538

400917
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

401137
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407377
type: Reaction
kinetic law: 431945
product: 431933
product: 431921
reactant: 431909
fast: false
reversible: false

431945
type: KineticLaw
local parameters: 569218
notes: k3*PKA_minus_active_slash_PKA_minus_phosph_minus_GEF_slash_PKA_minus_phosph_minus_GEF_cplx

569218
type: LocalParameter
units: 424878
value: 1.35E-14

431933
type: SpeciesReference
stoichiometry: 1.0
species: 402137

402137
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

431921
type: SpeciesReference
stoichiometry: 1.0
species: 402077

402077
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

431909
type: SpeciesReference
stoichiometry: 1.0
species: 402157

402157
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

402917
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 20.0
initial amount: NaN
in compartment: 400538

407697
type: Reaction
kinetic law: 432742
product: 432729
product: 432717
reactant: 432705
fast: false
reversible: false

432742
type: KineticLaw
local parameters: 569253
notes: k3*CaMKII_slash_tot_CaM_CaMKII_slash_CaM_act_286_slash_CaM_act_286_cplx

569253
type: LocalParameter
units: 424878
value: 7.5E-16

432729
type: SpeciesReference
stoichiometry: 1.0
species: 404317

404317
type: Species
constant: false
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

432717
type: SpeciesReference
stoichiometry: 1.0
species: 402637

402637
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

432705
type: SpeciesReference
stoichiometry: 1.0
species: 402737

402737
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405397
type: Reaction
kinetic law: 427177
product: 427165
reactant: 427153
notes: This reaction represents one of the big unknowns in CaMK-II biochemistry: what maintains the basal level of phosphorylation on thr 286 ? See Hanson and Schulman Ann Rev Biochem 1992 61:559-601, specially pg 580, for review. I have not been able to find any compelling mechanism in the literature, but fortunately the level of basal activity is well documented.
fast: false
reversible: true

427177
type: KineticLaw
local parameters: 568962
local parameters: 568959
notes: kf*CaMKII_slash_CaMKII-kb*CaMKII_slash_CaMKII_minus_thr286

568962
type: LocalParameter
units: 424878
value: 0.0

568959
type: LocalParameter
units: 424878
value: 4.5E-18

427165
type: SpeciesReference
stoichiometry: 1.0
species: 402677

427153
type: SpeciesReference
stoichiometry: 1.0
species: 402597

402597
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 70.0
initial amount: NaN
in compartment: 400538

405557
type: Reaction
kinetic law: 427553
product: 427541
reactant: 427529
reactant: 427517
notes: This process is probably much more complicated and involves CaM. However, as I can\'t find detailed info I am bundling this into a single step. Based on Steemer and Klee pg 6863, the Kact is 0.5 uM. kf/kb = 1/(0.5 * 6e5)^2 = 1.11e-11
fast: false
reversible: true

427553
type: KineticLaw
local parameters: 568994
local parameters: 568991
notes: kf*Ca^2*PP2B_slash_CaNAB_minus_Ca2-kb*CaNAB_minus_Ca4

568994
type: LocalParameter
units: 424878
value: 1.5E-15

568991
type: LocalParameter
units: 424914
value: 5.399946E-15

424950
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND

424938
type: SBMLUnit
exponent: -2.0
scale: -6
multipler: 1.0
kind: MOLE

424926
type: SBMLUnit
exponent: 3.0
scale: 0
multipler: 1.0
kind: LITRE

427541
type: SpeciesReference
stoichiometry: 1.0
species: 403237

403237
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427529
type: SpeciesReference
stoichiometry: 1.0
species: 403297

403297
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427517
type: SpeciesReference
stoichiometry: 2.0
species: 403917

400637
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0555555555555556
initial amount: NaN
in compartment: 400538

401617
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

401037
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406217
type: Reaction
kinetic law: 429104
product: 429092
product: 429080
product: 429068
reactant: 429056
fast: false
reversible: false

429104
type: KineticLaw
local parameters: 569106
notes: k3*PKC_minus_active_slash_PKC_minus_phosph_minus_ng_minus_CaM_slash_PKC_minus_phosph_minus_ng_minus_CaM_cplx

569106
type: LocalParameter
units: 424878
value: 5.25E-16

429092
type: SpeciesReference
stoichiometry: 1.0
species: 404297

404297
type: Species
constant: false
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

429080
type: SpeciesReference
stoichiometry: 1.0
species: 402957

429068
type: SpeciesReference
stoichiometry: 1.0
species: 402917

429056
type: SpeciesReference
stoichiometry: 1.0
species: 400717

400717
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405077
type: Reaction
kinetic law: 426485
product: 426473
reactant: 426460
notes: This is extremely slow (1e-4), but it is significant as so little GAP actually gets complexed with it that the total GTP turnover rises only by 2-3 X (see Gibbs et al, JBC 265(33) 20437-20422) and Eccleston et al JBC 268(36) 27012-27019 kf = 1e-4
fast: false
reversible: true

426485
type: KineticLaw
local parameters: 568902
local parameters: 568899
notes: kf*Ras_slash_GTP_minus_Ras-kb*Ras_slash_GDP_minus_Ras

568902
type: LocalParameter
units: 424878
value: 0.0

568899
type: LocalParameter
units: 424878
value: 1.5E-19

426473
type: SpeciesReference
stoichiometry: 1.0
species: 401997

401997
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.5
initial amount: NaN
in compartment: 400538

426460
type: SpeciesReference
stoichiometry: 1.0
species: 401977

401817
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405777
type: Reaction
kinetic law: 428087
product: 428075
reactant: 428063
reactant: 428051
notes: This has to be set to zero for matching the expts in vitro. In vivo we need to consider the inhibition though. kf = 1e-5 kb = 1
fast: false
reversible: true

428087
type: KineticLaw
local parameters: 569038
local parameters: 569035
notes: kf*PKA_minus_active*PKA_slash_PKA_minus_inhibitor-kb*PKA_slash_inhibited_minus_PKA

569038
type: LocalParameter
units: 424878
value: 1.5E-15

569035
type: LocalParameter
units: 424962
value: 9.000045E-14

428075
type: SpeciesReference
stoichiometry: 1.0
species: 403537

403537
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

428063
type: SpeciesReference
stoichiometry: 1.0
species: 403517

403517
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.25
initial amount: NaN
in compartment: 400538

428051
type: SpeciesReference
stoichiometry: 1.0
species: 402137

405377
type: Reaction
kinetic law: 427141
product: 427129
reactant: 427117
reactant: 427105
notes: Affinity is up 1000X. Time to release is about 20 sec, so the kb is OK at 0.1 This makes Kf around 1.6666e-3
fast: false
reversible: true

427141
type: KineticLaw
local parameters: 568958
local parameters: 568955
notes: kf*CaMKII_slash_CaMKII_minus_thr286*CaM_minus_Ca4-kb*CaMKII_slash_CaMKII_minus_thr286_star__minus_CaM

568958
type: LocalParameter
units: 424878
value: 1.5E-16

568955
type: LocalParameter
units: 424962
value: 1.500255E-12

427129
type: SpeciesReference
stoichiometry: 1.0
species: 402637

427117
type: SpeciesReference
stoichiometry: 1.0
species: 402217

402217
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427105
type: SpeciesReference
stoichiometry: 1.0
species: 402677

408237
type: Reaction
kinetic law: 434048
modifier: 434036
product: 434024
reactant: 434012
fast: false
reversible: false

434048
type: KineticLaw
local parameters: 569311
local parameters: 569308
notes: kcat*AC_slash_AC2_minus_Gs*AC_slash_ATP/(Km+AC_slash_ATP)

569311
type: LocalParameter
units: 424842
value: 20.0

424866
type: SBMLUnit
exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE

424854
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: LITRE

569308
type: LocalParameter
units: 424878
value: 2.7E-14

403637
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

434024
type: SpeciesReference
stoichiometry: 1.0
species: 403557

403557
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

434012
type: SpeciesReference
stoichiometry: 1.0
species: 404237

404237
type: Species
notes: ATP is present in all cells between 2 and 10 mM. See Lehninger.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 5000.0
initial amount: NaN
in compartment: 400538

401157
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

402857
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

403997
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408097
type: Reaction
kinetic law: 433708
product: 433696
product: 433684
reactant: 433671
fast: false
reversible: false

433708
type: KineticLaw
local parameters: 569292
notes: k3*PP2A_slash_PP2A_minus_dephosph_minus_I1_slash_PP2A_minus_dephosph_minus_I1_cplx

569292
type: LocalParameter
units: 424878
value: 9.0E-15

433696
type: SpeciesReference
stoichiometry: 1.0
species: 403177

433684
type: SpeciesReference
stoichiometry: 1.0
species: 403097

403097
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.8
initial amount: NaN
in compartment: 400538

433671
type: SpeciesReference
stoichiometry: 1.0
species: 403197

403197
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408337
type: Reaction
kinetic law: 434289
product: 434277
reactant: 434265
reactant: 434253
notes: This form has about twice the activity of the unphosphorylated form. See Sette et al JBC 269:28 18271-18274 1994. We\'ll ignore cGMP effects for now.
fast: false
reversible: true

434289
type: KineticLaw
local parameters: 569326
local parameters: 569325
notes: k1*cAMP*AC_slash_cAMP_minus_PDE_star_-k2*AC_slash_cAMP_minus_PDE_star__slash_PDE_star__slash_PDE_star__cplx

569326
type: LocalParameter
units: 424878
value: 1.2E-13

569325
type: LocalParameter
units: 424962
value: 7.56E-15

434277
type: SpeciesReference
stoichiometry: 1.0
species: 403797

403797
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

434265
type: SpeciesReference
stoichiometry: 1.0
species: 403777

434253
type: SpeciesReference
stoichiometry: 1.0
species: 403557

401557
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405937
type: Reaction
kinetic law: 428451
product: 428439
reactant: 428427
reactant: 428415
notes: 18 May 2003. This reaction is here to provide basal activity for MAPK as well as the potential for direct EGF stimulus without PKC activation. Based on model from FB/fb28c.g: the model used for MKP-1 turnover. The rates there were constrained by basal activity values.
fast: false
reversible: true

428451
type: KineticLaw
local parameters: 569070
local parameters: 569067
notes: kf*MAPK_slash_craf_minus_1*Ras_slash_GTP_minus_Ras-kb*MAPK_slash_Raf_minus_GTP_minus_Ras

569070
type: LocalParameter
units: 424878
value: 0.0

569067
type: LocalParameter
units: 424962
value: 0.0

428439
type: SpeciesReference
stoichiometry: 1.0
species: 401597

428427
type: SpeciesReference
stoichiometry: 1.0
species: 401977

428415
type: SpeciesReference
stoichiometry: 1.0
species: 401397

401397
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.5
initial amount: NaN
in compartment: 400538

407397
type: Reaction
kinetic law: 431994
product: 431982
reactant: 431970
reactant: 431958
notes: #s from Bramson et al CRC crit rev Biochem 15:2 93-124. They have a huge list of peptide substrates and I have chosen high-ish rates. These consts give too much PKA activity, so lower Vmax 1/3. Now, k1 = 3e-5, k2 = 36, k3 = 9 (still pretty fast). Also lower Km 1/3 so k1 = 1e-5 Cohen et al FEBS Lett 76:182-86 1977 say rate =30% PKA act on phosphokinase beta.
fast: false
reversible: true

431994
type: KineticLaw
local parameters: 569220
local parameters: 569219
notes: k1*PP1_slash_I1*PKA_minus_active-k2*PKA_minus_active_slash_PKA_minus_phosph_minus_I1_slash_PKA_minus_phosph_minus_I1_cplx

569220
type: LocalParameter
units: 424878
value: 5.4E-14

569219
type: LocalParameter
units: 424962
value: 9.000045E-15

431982
type: SpeciesReference
stoichiometry: 1.0
species: 402177

402177
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

431970
type: SpeciesReference
stoichiometry: 1.0
species: 402137

431958
type: SpeciesReference
stoichiometry: 1.0
species: 403097

404897
type: Reaction
kinetic law: 426061
product: 426048
reactant: 426036
notes: From Berstein et al JBC 267:12 8081-8088 1992, kcat for GTPase activity of Gq is only 0.8/min
fast: false
reversible: true

426061
type: KineticLaw
local parameters: 568866
local parameters: 568863
notes: kf*G_star_GTP-kb*G_star_GDP

568866
type: LocalParameter
units: 424878
value: 0.0

568863
type: LocalParameter
units: 424878
value: 1.995E-17

426048
type: SpeciesReference
stoichiometry: 1.0
species: 401257

401257
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426036
type: SpeciesReference
stoichiometry: 1.0
species: 401237

400797
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408057
type: Reaction
kinetic law: 433611
product: 433599
product: 433587
reactant: 433575
fast: false
reversible: false

433611
type: KineticLaw
local parameters: 569289
notes: k3*CaM_po_Ca_pc_n_minus_CaNAB_slash_dephosph_minus_PP1_minus_I_star__slash_dephosph_minus_PP1_minus_I_star__cplx

569289
type: LocalParameter
units: 424878
value: 5.1E-16

433599
type: SpeciesReference
stoichiometry: 1.0
species: 404357

433587
type: SpeciesReference
stoichiometry: 1.0
species: 403157

403157
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

433575
type: SpeciesReference
stoichiometry: 1.0
species: 403077

403077
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

404937
type: Reaction
kinetic law: 426158
product: 426146
reactant: 426134
reactant: 426122
notes: From Fay et al kb3 = kb = 1.06e-3 which is rather slow. k+1 = kf = 2.8e7 /M/sec= 4.67e-5/sec use 5e-5. However, the Kd from Martin et al may be more appropriate, as this is Glu not the system from Fay. kf = 2.8e-5, kb = 10 Let us compromise. since we have the Fay model, keep kf = k+1 = 2.8e-5. But kb (k-3) is .01 * k-1 from Fay. Scaling by .01, kb = .01 * 10 = 0.1
fast: false
reversible: true

426158
type: KineticLaw
local parameters: 568874
local parameters: 568871
notes: kf*Glu*Gq_slash_Rec_minus_Gq-kb*Gq_slash_Rec_minus_Glu_minus_Gq

568874
type: LocalParameter
units: 424878
value: 1.5E-16

568871
type: LocalParameter
units: 424962
value: 2.520045E-14

426146
type: SpeciesReference
stoichiometry: 1.0
species: 401357

401357
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426134
type: SpeciesReference
stoichiometry: 1.0
species: 401337

401337
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426122
type: SpeciesReference
stoichiometry: 1.0
species: 404117

404117
type: Species
notes: Varying the amount of (steady state) glu between .01 uM and up, the final amount of G*GTP complex does not change much. This means that the system should be reasonably robust wr to the amount of glu in the synaptic cleft. It would be nice to know how fast it is removed.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407477
type: Reaction
kinetic law: 432188
product: 432176
reactant: 432164
reactant: 432152
fast: false
reversible: true

432188
type: KineticLaw
local parameters: 569229
local parameters: 569228
notes: k1*Ras_slash_GDP_minus_Ras*Shc_star__dot_Sos_dot_Grb2-k2*Shc_star__dot_Sos_dot_Grb2_slash_Sos_dot_Ras_GEF_slash_Sos_dot_Ras_GEF_cplx

569229
type: LocalParameter
units: 424878
value: 1.2E-16

569228
type: LocalParameter
units: 424962
value: 2.97E-16

432176
type: SpeciesReference
stoichiometry: 1.0
species: 402257

402257
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

432164
type: SpeciesReference
stoichiometry: 1.0
species: 402237

402237
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

432152
type: SpeciesReference
stoichiometry: 1.0
species: 401997

407077
type: Reaction
kinetic law: 431222
product: 431210
reactant: 431198
reactant: 431186
notes: See: Kyriakis et al Nature 358 pp 417-421 1992 Ahn et al Curr Op Cell Biol 4:992-999 1992 for this pathway. See parent PPhosphatase2A for parms.
fast: false
reversible: true

569192
type: LocalParameter
units: 424878
value: 3.6E-14

569189
type: LocalParameter
units: 424962
value: 2.87415E-15

431210
type: SpeciesReference
stoichiometry: 1.0
species: 401817

431198
type: SpeciesReference
stoichiometry: 1.0
species: 401777

431186
type: SpeciesReference
stoichiometry: 1.0
species: 401517

408157
type: Reaction
kinetic law: 433854
product: 433842
reactant: 433830
reactant: 433818
notes: The rates here are so slow I do not know if we should even bother with this enz reacn. These numbers are from Liu and Storm. Other refs suggest that the Km stays the same but the Vmax goes to 10% of the CaM stim levels. Prev: k1=2.2e-9, k2 = 0.0052, k3 = 0.0013 New : k1=5.7e-8, k2=.136, k3=.034
fast: false
reversible: true

433854
type: KineticLaw
local parameters: 569297
local parameters: 569296
notes: k1*PP1_slash_I1_star_*CaNAB_minus_Ca4-k2*CaNAB_minus_Ca4_slash_dephosph_inhib1_noCaM_slash_dephosph_inhib1_noCaM_cplx

569297
type: LocalParameter
units: 424878
value: 2.04E-16

569296
type: LocalParameter
units: 424962
value: 5.13E-17

433842
type: SpeciesReference
stoichiometry: 1.0
species: 403257

403257
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

433830
type: SpeciesReference
stoichiometry: 1.0
species: 403237

433818
type: SpeciesReference
stoichiometry: 1.0
species: 403117

403117
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.001
initial amount: NaN
in compartment: 400538

402417
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407777
type: Reaction
kinetic law: 432936
product: 432924
product: 432912
reactant: 432900
fast: false
reversible: false

432936
type: KineticLaw
local parameters: 569262
notes: k3*CaMKII_slash_tot_autonomous_CaMKII_slash_auton_286_slash_auton_286_cplx

569262
type: LocalParameter
units: 424878
value: 7.5E-16

432924
type: SpeciesReference
stoichiometry: 1.0
species: 404337

404337
type: Species
constant: false
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

432912
type: SpeciesReference
stoichiometry: 1.0
species: 402637

432900
type: SpeciesReference
stoichiometry: 1.0
species: 402777

402777
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406277
type: Reaction
kinetic law: 429250
product: 429238
reactant: 429226
reactant: 429214
notes: 10 x raise oct22 12 x oct 24, set k2 = 4 * k3
fast: false
reversible: true

429250
type: KineticLaw
local parameters: 569114
local parameters: 569111
notes: k1*PLA2_slash_APC*PLA2_slash_PLA2_minus_Ca_star_-k2*PLA2_slash_PLA2_minus_Ca_star__slash_kenz_slash_kenz_cplx

569114
type: LocalParameter
units: 424878
value: 3.24E-14

569111
type: LocalParameter
units: 424962
value: 2.025E-15

429238
type: SpeciesReference
stoichiometry: 1.0
species: 400797

429226
type: SpeciesReference
stoichiometry: 1.0
species: 400777

400777
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

429214
type: SpeciesReference
stoichiometry: 1.0
species: 404077

404077
type: Species
notes: arachodonylphosphatidylcholine is the favoured substrate from Wijkander and Sundler, JBC 202 pp 873-880, 1991. Their assay used 30 uM substrate, which is what the kinetics in this model are based on. For the later model we should locate a more realistic value for APC.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 30.0
initial amount: NaN
in compartment: 400538

404777
type: Reaction
kinetic law: 425778
product: 425765
product: 425752
reactant: 425740
notes: This process is assumed to be directly caused by the inactivation of the G*GTP to G*GDP. Hence, kf = .013 /sec = 0.8/min, same as the rate for Inact-G. kb = 0 since this is irreversible. We may be interested in studying the role of PLC as a GAP. If so, the kf would be faster here than in Inact-G
fast: false
reversible: true

425778
type: KineticLaw
local parameters: 568842
local parameters: 568839
notes: kf*PLCbeta_slash_PLC_minus_Ca_minus_Gq-kb*G_star_GDP*PLCbeta_slash_PLC_minus_Ca

568842
type: LocalParameter
units: 424962
value: 0.0

568839
type: LocalParameter
units: 424878
value: 1.995E-17

425765
type: SpeciesReference
stoichiometry: 1.0
species: 401117

425752
type: SpeciesReference
stoichiometry: 1.0
species: 401257

425740
type: SpeciesReference
stoichiometry: 1.0
species: 401157

401837
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405657
type: Reaction
kinetic law: 427797
product: 427785
reactant: 427773
reactant: 427760
notes: Hasler et al FASEB J 6:2734-2741 1992 say Kd =1e-7M for type II, 5.6e-8 M for type I. Take mean which comes to 2e-13 #/cell Smith et al PNAS USA 78:3 1591-1595 1981 have better data. First kf/kb=2.1e7/M = 3.5e-5 (#/cell). Ogreid and Doskeland Febs Lett 129:2 287-292 1981 have figs suggesting time course of complete assoc is < 1 min.
fast: false
reversible: true

427797
type: KineticLaw
local parameters: 569014
local parameters: 569011
notes: kf*PKA_slash_R2C2*cAMP-kb*PKA_slash_R2C2_minus_cAMP

569014
type: LocalParameter
units: 424878
value: 4.95E-14

569011
type: LocalParameter
units: 424962
value: 8.1E-14

427785
type: SpeciesReference
stoichiometry: 1.0
species: 403397

403397
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427773
type: SpeciesReference
stoichiometry: 1.0
species: 403557

427760
type: SpeciesReference
stoichiometry: 1.0
species: 403377

403377
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.5
initial amount: NaN
in compartment: 400538

407457
type: Reaction
kinetic law: 432140
product: 432127
product: 432115
reactant: 432103
fast: false
reversible: false

432140
type: KineticLaw
local parameters: 569227
notes: k3*PKA_minus_active_slash_phosph_minus_PDE_slash_phosph_minus_PDE_cplx

569227
type: LocalParameter
units: 424878
value: 1.35E-14

432127
type: SpeciesReference
stoichiometry: 1.0
species: 402137

432115
type: SpeciesReference
stoichiometry: 1.0
species: 403777

432103
type: SpeciesReference
stoichiometry: 1.0
species: 402197

402197
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406377
type: Reaction
kinetic law: 429492
product: 429480
product: 429468
reactant: 429456
fast: false
reversible: false

429492
type: KineticLaw
local parameters: 569121
notes: k3*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

569121
type: LocalParameter
units: 424878
value: 5.4E-14

429480
type: SpeciesReference
stoichiometry: 1.0
species: 400857

400857
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

429468
type: SpeciesReference
stoichiometry: 1.0
species: 400657

400657
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

429456
type: SpeciesReference
stoichiometry: 1.0
species: 400877

400877
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406077
type: Reaction
kinetic law: 428752
product: 428740
reactant: 428728
reactant: 428716
notes: Rate consts copied from PCK-act-raf This reaction inactivates GAP. The idea is from the Boguski and McCormick review.
fast: false
reversible: true

428752
type: KineticLaw
local parameters: 569093
local parameters: 569092
notes: k1*Ras_slash_GAP*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_inact_minus_GAP_slash_PKC_minus_inact_minus_GAP_cplx

569093
type: LocalParameter
units: 424878
value: 2.4E-14

569092
type: LocalParameter
units: 424962
value: 9.000045E-15

428740
type: SpeciesReference
stoichiometry: 1.0
species: 400677

400677
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

428728
type: SpeciesReference
stoichiometry: 1.0
species: 404297

428716
type: SpeciesReference
stoichiometry: 1.0
species: 402037

402037
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.01
initial amount: NaN
in compartment: 400538

405157
type: Reaction
kinetic law: 426656
product: 426644
reactant: 426632
reactant: 426620
notes: Affinity of EGFR for EGF is complex: depends on [EGFR]. We\'ll assume fixed [EGFR] and use exptal affinity ~20 nM (see Sherrill and Kyte Biochem 1996 35 5705-5718, Berkers et al JBC 266:2 922-927 1991, Sorokin et al JBC 269:13 9752-9759 1994). Tau =~2 min (Davis et al JBC 263:11 5373-5379 1988) or Berkers Kass = 6.2e5/M/sec, Kdiss=3.5e-4/sec. Sherrill and Kyte have Hill Coeff=1.7
fast: false
reversible: true

426656
type: KineticLaw
local parameters: 568918
local parameters: 568915
notes: kf*EGFR_slash_EGFR*EGFR_slash_EGF-kb*EGFR_slash_L_dot_EGFR

568918
type: LocalParameter
units: 424878
value: 3.75E-16

568915
type: LocalParameter
units: 424962
value: 6.300045E-15

426644
type: SpeciesReference
stoichiometry: 1.0
species: 402297

402297
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426632
type: SpeciesReference
stoichiometry: 1.0
species: 404217

404217
type: Species
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426620
type: SpeciesReference
stoichiometry: 1.0
species: 402277

402277
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.166666666666667
initial amount: NaN
in compartment: 400538

405477
type: Reaction
kinetic law: 427372
product: 427359
reactant: 427347
reactant: 427335
notes: Surprisingly, no direct info on rates from neurogranin at this time. These rates are based on GAP-43 binding studies. As GAP-43 and neurogranin share near identity in the CaM/PKC binding regions, and also similarity in phosph and dephosph rates, I am borrowing GAP-43 kinetic info. See Alexander et al JBC 262:13 6108-6113 1987
fast: false
reversible: true

427372
type: KineticLaw
local parameters: 568978
local parameters: 568975
notes: kf*CaM_slash_neurogranin*CaM_slash_CaM-kb*CaM_slash_neurogranin_minus_CaM

568978
type: LocalParameter
units: 424878
value: 1.5E-15

568975
type: LocalParameter
units: 424962
value: 4.499955E-16

427359
type: SpeciesReference
stoichiometry: 1.0
species: 402937

402937
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427347
type: SpeciesReference
stoichiometry: 1.0
species: 402917

427335
type: SpeciesReference
stoichiometry: 1.0
species: 402977

402977
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 10.0
initial amount: NaN
in compartment: 400538

405957
type: Reaction
kinetic law: 428488
product: 428475
reactant: 428463
fast: false
reversible: true

428488
type: KineticLaw
local parameters: 569074
local parameters: 569071
notes: kf*Ca_input-kb*Ca

569074
type: LocalParameter
units: 424878
value: 1.5E-13

569071
type: LocalParameter
units: 424878
value: 1.5E-13

428475
type: SpeciesReference
stoichiometry: 1.0
species: 403917

428463
type: SpeciesReference
stoichiometry: 1.0
species: 403937

403937
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405677
type: Reaction
kinetic law: 427845
product: 427833
reactant: 427821
reactant: 427809
notes: For now let us set this to the same Km (1e-7M) as site B. This gives kf/kb = .7e-7M * 1e6 / (6e5^2) : 1/(6e5^2) = 2e-13:2.77e-12 Smith et al have better values. They say that this is cooperative, so the consts are now kf/kb =8.3e-4
fast: false
reversible: true

427845
type: KineticLaw
local parameters: 569018
local parameters: 569015
notes: kf*PKA_slash_R2C2_minus_cAMP*cAMP-kb*PKA_slash_R2C2_minus_cAMP2

569018
type: LocalParameter
units: 424878
value: 4.95E-14

569015
type: LocalParameter
units: 424962
value: 8.1E-14

427833
type: SpeciesReference
stoichiometry: 1.0
species: 403417

403417
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427821
type: SpeciesReference
stoichiometry: 1.0
species: 403557

427809
type: SpeciesReference
stoichiometry: 1.0
species: 403397

407177
type: Reaction
kinetic law: 431462
product: 431450
product: 431438
reactant: 431426
fast: false
reversible: false

569199
type: LocalParameter
units: 424878
value: 9.0E-15

431450
type: SpeciesReference
stoichiometry: 1.0
species: 401777

431438
type: SpeciesReference
stoichiometry: 1.0
species: 401417

431426
type: SpeciesReference
stoichiometry: 1.0
species: 401857

401857
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408197
type: Reaction
kinetic law: 433951
modifier: 433939
product: 433926
reactant: 433914
fast: false
reversible: false

433951
type: KineticLaw
local parameters: 569303
local parameters: 569300
notes: kcat*AC_slash_AC1_minus_CaM*AC_slash_ATP/(Km+AC_slash_ATP)

569303
type: LocalParameter
units: 424842
value: 20.0

569300
type: LocalParameter
units: 424878
value: 2.7E-14

433926
type: SpeciesReference
stoichiometry: 1.0
species: 403557

433914
type: SpeciesReference
stoichiometry: 1.0
species: 404237

401497
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407737
type: Reaction
kinetic law: 432839
product: 432827
product: 432815
reactant: 432803
fast: false
reversible: false

432839
type: KineticLaw
local parameters: 569256
notes: k3*CaMKII_slash_tot_autonomous_CaMKII_slash_auton_305_slash_auton_305_cplx

569256
type: LocalParameter
units: 424878
value: 9.0E-15

432827
type: SpeciesReference
stoichiometry: 1.0
species: 404337

432815
type: SpeciesReference
stoichiometry: 1.0
species: 402657

402657
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

432803
type: SpeciesReference
stoichiometry: 1.0
species: 402757

402757
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408277
type: Reaction
kinetic law: 434145
modifier: 434133
product: 434121
reactant: 434108
fast: false
reversible: false

434145
type: KineticLaw
local parameters: 569319
local parameters: 569316
notes: kcat*AC_slash_AC2_star__minus_Gs*AC_slash_ATP/(Km+AC_slash_ATP)

569319
type: LocalParameter
units: 424842
value: 60.0

569316
type: LocalParameter
units: 424878
value: 8.1E-14

403717
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

434121
type: SpeciesReference
stoichiometry: 1.0
species: 403557

434108
type: SpeciesReference
stoichiometry: 1.0
species: 404237

404457
type: Reaction
kinetic law: 425071
product: 425059
reactant: 425047
reactant: 425035
notes: Need est of rate of assoc of Ca and PKC. Assume it is fast The original parameter-searched kf of 439.4 has been scaled by 1/6e8 to account for change of units to n. Kf now 8.16e-7, kb=.6085 Raised kf to 1e-6 to match Ca curve, kb to .5
fast: false
reversible: true

425071
type: KineticLaw
local parameters: 568786
local parameters: 568785
notes: kf*PKC_slash_PKC_minus_cytosolic*Ca-kb*PKC_slash_PKC_minus_Ca

568786
type: LocalParameter
units: 424878
value: 7.5E-16

568785
type: LocalParameter
units: 424962
value: 9.000045E-16

425059
type: SpeciesReference
stoichiometry: 1.0
species: 400558

425047
type: SpeciesReference
stoichiometry: 1.0
species: 403917

425035
type: SpeciesReference
stoichiometry: 1.0
species: 400618

400618
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 400538

408477
type: Reaction
kinetic law: 434628
product: 434616
product: 434604
reactant: 434592
fast: false
reversible: false

434628
type: KineticLaw
local parameters: 569339
notes: k3*PKM_slash_PKM_synthesis_slash_kenz_slash_kenz_cplx

569339
type: LocalParameter
units: 424878
value: 7.5E-17

434616
type: SpeciesReference
stoichiometry: 1.0
species: 403977

434604
type: SpeciesReference
stoichiometry: 1.0
species: 400637

434592
type: SpeciesReference
stoichiometry: 1.0
species: 403997

407557
type: Reaction
kinetic law: 432380
product: 432368
reactant: 432356
reactant: 432344
notes: Rates from Okada et al JBC 270:35 pp 20737 1995 Km = 0.70 to 0.85 uM, Vmax = 4.4 to 5.0 pmol/min. Unfortunately the amount of enzyme is not known, the prep is only partially purified. Time course of phosph is max within 30 sec, falls back within 20 min. Ref: Sasaoka et al JBC 269:51 32621 1994. Use k3 = 0.1 based on this tau.
fast: false
reversible: true

432380
type: KineticLaw
local parameters: 569235
local parameters: 569234
notes: k1*EGFR_slash_SHC*EGFR_slash_L_dot_EGFR-k2*EGFR_slash_L_dot_EGFR_slash_phosph_Shc_slash_phosph_Shc_cplx

569235
type: LocalParameter
units: 424878
value: 1.2E-15

569234
type: LocalParameter
units: 424962
value: 1.799955E-15

432368
type: SpeciesReference
stoichiometry: 1.0
species: 402337

402337
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

432356
type: SpeciesReference
stoichiometry: 1.0
species: 402297

432344
type: SpeciesReference
stoichiometry: 1.0
species: 402357

402357
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.5
initial amount: NaN
in compartment: 400538

404557
type: Reaction
kinetic law: 425292
product: 425280
reactant: 425268
reactant: 425255
notes: Leslie and Channon BBA 1045 (1990) 261-270 fig6 pp267.
fast: false
reversible: true

425292
type: KineticLaw
local parameters: 568798
local parameters: 568795
notes: kf*PLA2_slash_PLA2_minus_cytosolic*Ca-kb*PLA2_slash_PLA2_minus_Ca_star_

568798
type: LocalParameter
units: 424878
value: 1.5E-16

568795
type: LocalParameter
units: 424962
value: 1.499985E-15

425280
type: SpeciesReference
stoichiometry: 1.0
species: 400777

425268
type: SpeciesReference
stoichiometry: 1.0
species: 403917

425255
type: SpeciesReference
stoichiometry: 1.0
species: 400757

405437
type: Reaction
kinetic law: 427274
product: 427262
reactant: 427250
reactant: 427238
notes: K3 = 21.5, K4 = 2.8. Assuming that the K4 step happens first, we get kb/kf = 2.8 uM = 1.68e6 so kf =6e-6 assuming kb = 10
fast: false
reversible: true

427274
type: KineticLaw
local parameters: 568970
local parameters: 568967
notes: kf*CaM_minus_TR2_minus_Ca2*Ca-kb*CaM_minus_Ca3

568970
type: LocalParameter
units: 424878
value: 1.5E-14

568967
type: LocalParameter
units: 424962
value: 5.4E-15

427262
type: SpeciesReference
stoichiometry: 1.0
species: 402997

402997
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427250
type: SpeciesReference
stoichiometry: 1.0
species: 403917

427238
type: SpeciesReference
stoichiometry: 1.0
species: 403017

407877
type: Reaction
kinetic law: 433176
product: 433164
reactant: 433152
reactant: 433140
fast: false
reversible: true

433176
type: KineticLaw
local parameters: 569270
local parameters: 569269
notes: k1*CaMKII_slash_CaMKII_star__star__star_*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr286c_slash_Deph_minus_thr286c_cplx

569270
type: LocalParameter
units: 424878
value: 2.1E-15

569269
type: LocalParameter
units: 424962
value: 5.147955E-16

433164
type: SpeciesReference
stoichiometry: 1.0
species: 402877

402877
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

433152
type: SpeciesReference
stoichiometry: 1.0
species: 402797

433140
type: SpeciesReference
stoichiometry: 1.0
species: 402657

406957
type: Reaction
kinetic law: 430930
product: 430918
reactant: 430906
reactant: 430894
notes: The original kinetics have been modified to obey the k2 = 4 * k3 rule, while keeping kcat and Km fixed. As noted in the NOTES, the only constraining data point is the time course of MAPK dephosphorylation, which this model satisfies. It would be nice to have more accurate estimates of rate consts and MKP-1 levels from the literature. Effective Km : 67 nM kcat = 1.43 umol/min/mg
fast: false
reversible: true

430930
type: KineticLaw
local parameters: 569180
local parameters: 569179
notes: k1*MAPK_slash_MAPK_minus_tyr*MKP_minus_1-k2*MKP_minus_1_slash_MKP1_minus_tyr_minus_deph_slash_MKP1_minus_tyr_minus_deph_cplx

569180
type: LocalParameter
units: 424878
value: 2.4E-14

569179
type: LocalParameter
units: 424962
value: 4.28571E-15

430918
type: SpeciesReference
stoichiometry: 1.0
species: 401737

401737
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

430906
type: SpeciesReference
stoichiometry: 1.0
species: 401717

401717
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.02
initial amount: NaN
in compartment: 400538

430894
type: SpeciesReference
stoichiometry: 1.0
species: 401497

406157
type: Reaction
kinetic law: 428947
product: 428935
reactant: 428923
reactant: 428911
notes: Rates from Huang et al ABB 305:2 570-580 1993
fast: false
reversible: true

428947
type: KineticLaw
local parameters: 569102
local parameters: 569099
notes: k1*CaM_slash_neurogranin*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_phosph_minus_neurogranin_slash_PKC_minus_phosph_minus_neurogranin_cplx

569102
type: LocalParameter
units: 424878
value: 3.51E-15

569099
type: LocalParameter
units: 424962
value: 1.529955E-16

428935
type: SpeciesReference
stoichiometry: 1.0
species: 400697

400697
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

428923
type: SpeciesReference
stoichiometry: 1.0
species: 404297

428911
type: SpeciesReference
stoichiometry: 1.0
species: 402977

402397
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406677
type: Reaction
kinetic law: 430242
product: 430230
reactant: 430218
reactant: 430206
notes: The actual MAPKK is 2 forms from Seger et al JBC 267:20 14373(1992) Vmax = 150nmol/min/mg From Haystead et al FEBS 306(1):17-22 we get Km=46.6nM for at least one of the phosphs. Putting these together: k3=0.15/sec, scale to get k2=0.6. k1=0.75/46.6nM=2.7e-5
fast: false
reversible: true

430242
type: KineticLaw
local parameters: 569153
local parameters: 569152
notes: k1*MAPK_slash_MAPK*MAPK_slash_MAPKK_star_-k2*MAPK_slash_MAPKK_star__slash_MAPKKtyr_slash_MAPKKtyr_cplx

569153
type: LocalParameter
units: 424878
value: 1.8E-15

569152
type: LocalParameter
units: 424962
value: 4.86E-14

430230
type: SpeciesReference
stoichiometry: 1.0
species: 401537

401537
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

430218
type: SpeciesReference
stoichiometry: 1.0
species: 401517

430206
type: SpeciesReference
stoichiometry: 1.0
species: 401457

401457
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 3.6
initial amount: NaN
in compartment: 400538

403357
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405457
type: Reaction
kinetic law: 427323
product: 427310
reactant: 427298
reactant: 427286
notes: Use K3 = 21.5 uM here from Stemmer and Klee table 3. kb/kf =21.5 * 6e5 so kf = 7.75e-7, kb = 10
fast: false
reversible: true

427323
type: KineticLaw
local parameters: 568974
local parameters: 568971
notes: kf*CaM_minus_Ca3*Ca-kb*CaM_minus_Ca4

568974
type: LocalParameter
units: 424878
value: 1.5E-14

568971
type: LocalParameter
units: 424962
value: 6.975045E-16

427310
type: SpeciesReference
stoichiometry: 1.0
species: 402217

427298
type: SpeciesReference
stoichiometry: 1.0
species: 403917

427286
type: SpeciesReference
stoichiometry: 1.0
species: 402997

406137
type: Reaction
kinetic law: 428899
product: 428886
product: 428874
reactant: 428862
fast: false
reversible: false

428899
type: KineticLaw
local parameters: 569097
notes: k3*PKC_minus_active_slash_PKC_minus_act_minus_GEF_slash_PKC_minus_act_minus_GEF_cplx

569097
type: LocalParameter
units: 424878
value: 6.0E-15

428886
type: SpeciesReference
stoichiometry: 1.0
species: 404297

428874
type: SpeciesReference
stoichiometry: 1.0
species: 401937

401937
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

428862
type: SpeciesReference
stoichiometry: 1.0
species: 400678

400678
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405537
type: Reaction
kinetic law: 427505
product: 427493
product: 427481
reactant: 427469
notes: Let us assume that the equil in this case is very far over to the right. This is probably safe.
fast: false
reversible: true

427505
type: KineticLaw
local parameters: 568990
local parameters: 568987
notes: kf*PP1_slash_PP1_minus_I1-kb*PP1_minus_active*PP1_slash_I1

568990
type: LocalParameter
units: 424962
value: 0.0

568987
type: LocalParameter
units: 424878
value: 1.5E-15

427493
type: SpeciesReference
stoichiometry: 1.0
species: 403097

427481
type: SpeciesReference
stoichiometry: 1.0
species: 402797

427469
type: SpeciesReference
stoichiometry: 1.0
species: 403157

405917
type: Reaction
kinetic law: 428403
product: 428391
reactant: 428379
reactant: 428367
notes: For olf epi PDE1, affinity is 7 nM. Assume same for brain. Reaction should be pretty fast. Assume kb = 5/sec. Then kf = 5 / (0.007 * 6e5) = 1.2e-3
fast: false
reversible: true

428403
type: KineticLaw
local parameters: 569066
local parameters: 569063
notes: kf*AC_slash_PDE1*CaM_minus_Ca4-kb*AC_slash_CaM_dot_PDE1

569066
type: LocalParameter
units: 424878
value: 7.5E-15

569063
type: LocalParameter
units: 424962
value: 1.08E-12

428391
type: SpeciesReference
stoichiometry: 1.0
species: 403857

403857
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

428379
type: SpeciesReference
stoichiometry: 1.0
species: 402217

428367
type: SpeciesReference
stoichiometry: 1.0
species: 403817

402117
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

403617
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

401917
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.1
initial amount: NaN
in compartment: 400538

408517
type: Reaction
kinetic law: 434725
product: 434713
product: 434701
reactant: 434689
fast: false
reversible: false

434725
type: KineticLaw
local parameters: 569342
notes: k3*PKM_slash_Ca_dot_detector_complex_slash_kenz_slash_kenz_cplx

569342
type: LocalParameter
units: 424878
value: 3.0E-16

434713
type: SpeciesReference
stoichiometry: 1.0
species: 404017

404017
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

434701
type: SpeciesReference
stoichiometry: 1.0
species: 403977

434689
type: SpeciesReference
stoichiometry: 1.0
species: 404037

404037
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406637
type: Reaction
kinetic law: 430133
product: 430121
reactant: 430109
reactant: 430097
notes: From Sternweis et al, Phil Trans R Soc Lond 1992, and the values from other refs eg Homma et al JBC 263(14) pp6592 1988 match. k1 = 5e-5/sec k2 = 240/sec; now 120/sec k3 = 60/sec; now 30/sec Note that the wording in Sternweis et al is ambiguous wr. to the Km for Gq vs non-Gq states of PLC. K1 is still a bit too low. Raise to 7e-5 9 Jun 1996: k1 was 0.0002, changed to 5e-5
fast: false
reversible: true

430133
type: KineticLaw
local parameters: 569150
local parameters: 569147
notes: k1*PIP2*PLCbeta_slash_PLC_minus_Ca_minus_Gq-k2*PLCbeta_slash_PLC_minus_Ca_minus_Gq_slash_PLCb_minus_Ca_minus_Gq_slash_PLCb_minus_Ca_minus_Gq_cplx

569150
type: LocalParameter
units: 424878
value: 2.88E-13

569147
type: LocalParameter
units: 424962
value: 7.199955E-14

430121
type: SpeciesReference
stoichiometry: 1.0
species: 401177

401177
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

430109
type: SpeciesReference
stoichiometry: 1.0
species: 401157

430097
type: SpeciesReference
stoichiometry: 1.0
species: 404177

404177
type: Species
constant: true
boundary condition: true
has only substance units: false
initial concentration: 10.0
initial amount: NaN
in compartment: 400538

405757
type: Reaction
kinetic law: 428039
product: 428027
product: 428015
reactant: 428003
fast: false
reversible: true

428039
type: KineticLaw
local parameters: 569034
local parameters: 569031
notes: kf*PKA_slash_R2C_minus_cAMP4-kb*PKA_minus_active*PKA_slash_R2_minus_cAMP4

569034
type: LocalParameter
units: 424962
value: 2.7E-14

569031
type: LocalParameter
units: 424878
value: 9.0E-14

428027
type: SpeciesReference
stoichiometry: 1.0
species: 403497

403497
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

428015
type: SpeciesReference
stoichiometry: 1.0
species: 402137

428003
type: SpeciesReference
stoichiometry: 1.0
species: 403477

403477
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408437
type: Reaction
kinetic law: 434532
product: 434520
product: 434508
reactant: 434496
fast: false
reversible: false

434532
type: KineticLaw
local parameters: 569333
notes: k3*AC_slash_CaM_dot_PDE1_slash_CaM_dot_PDE1_slash_CaM_dot_PDE1_cplx

569333
type: LocalParameter
units: 424878
value: 1.5E-14

434520
type: SpeciesReference
stoichiometry: 1.0
species: 403857

434508
type: SpeciesReference
stoichiometry: 1.0
species: 403697

434496
type: SpeciesReference
stoichiometry: 1.0
species: 403877

403877
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407297
type: Reaction
kinetic law: 431752
product: 431740
product: 431728
reactant: 431716
fast: false
reversible: false

431752
type: KineticLaw
local parameters: 569211
notes: k3*Ras_slash_GAP_slash_GAP_minus_inact_minus_ras_slash_GAP_minus_inact_minus_ras_cplx

569211
type: LocalParameter
units: 424878
value: 1.5E-14

431740
type: SpeciesReference
stoichiometry: 1.0
species: 402037

431728
type: SpeciesReference
stoichiometry: 1.0
species: 401997

431716
type: SpeciesReference
stoichiometry: 1.0
species: 402057

402057
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

401577
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405857
type: Reaction
kinetic law: 428269
product: 428257
reactant: 428245
reactant: 428233
notes: Half-max 8nM from Tang et al JBC266:13 8595-8603 kb/kf = 8 nM = 4800#/cell so kf = kb * 2.08e-4
fast: false
reversible: true

428269
type: KineticLaw
local parameters: 569054
local parameters: 569051
notes: kf*Gs_minus_alpha*AC_slash_AC1-kb*AC_slash_AC1_minus_Gs

569054
type: LocalParameter
units: 424878
value: 1.5E-15

569051
type: LocalParameter
units: 424962
value: 1.89E-13

428257
type: SpeciesReference
stoichiometry: 1.0
species: 403677

403677
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

428245
type: SpeciesReference
stoichiometry: 1.0
species: 403597

403597
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.02
initial amount: NaN
in compartment: 400538

428233
type: SpeciesReference
stoichiometry: 1.0
species: 403897

403897
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406457
type: Reaction
kinetic law: 429686
product: 429674
product: 429662
reactant: 429650
fast: false
reversible: false

429686
type: KineticLaw
local parameters: 569130
notes: k3*PLA2_slash_PLA2_star__minus_Ca_slash_kenz_slash_kenz_cplx

569130
type: LocalParameter
units: 424878
value: 1.8E-13

429674
type: SpeciesReference
stoichiometry: 1.0
species: 400937

400937
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

429662
type: SpeciesReference
stoichiometry: 1.0
species: 400657

429650
type: SpeciesReference
stoichiometry: 1.0
species: 400957

400957
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407937
type: Reaction
kinetic law: 433322
product: 433310
product: 433298
reactant: 433285
fast: false
reversible: false

433322
type: KineticLaw
local parameters: 569277
notes: k3*PP1_minus_active_slash_Deph_thr286b_slash_Deph_thr286b_cplx

569277
type: LocalParameter
units: 424878
value: 5.25E-16

433310
type: SpeciesReference
stoichiometry: 1.0
species: 402797

433298
type: SpeciesReference
stoichiometry: 1.0
species: 402597

433285
type: SpeciesReference
stoichiometry: 1.0
species: 402897

402897
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

404997
type: Reaction
kinetic law: 426315
product: 426303
reactant: 426291
reactant: 426279
notes: The rate consts give a total binding affinity of only
fast: false
reversible: true

426315
type: KineticLaw
local parameters: 568886
local parameters: 568883
notes: kf*Gq_slash_Rec_minus_Gq*Gq_slash_mGluRAntag-kb*Gq_slash_Blocked_minus_rec_minus_Gq

568886
type: LocalParameter
units: 424878
value: 1.5E-17

568883
type: LocalParameter
units: 424962
value: 9.000045E-14

426303
type: SpeciesReference
stoichiometry: 1.0
species: 401377

401377
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426291
type: SpeciesReference
stoichiometry: 1.0
species: 404197

404197
type: Species
notes: I am implementing this as acting only on the Rec-Gq complex, based on a more complete model PLC_Gq48.g which showed that the binding to the rec alone contributed only a small amount.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426279
type: SpeciesReference
stoichiometry: 1.0
species: 401337

425023
type: SBMLUnit
exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE

406657
type: Reaction
kinetic law: 430194
product: 430182
product: 430169
product: 430157
reactant: 430145
fast: false
reversible: false

430194
type: KineticLaw
local parameters: 569151
notes: k3*PLCbeta_slash_PLC_minus_Ca_minus_Gq_slash_PLCb_minus_Ca_minus_Gq_slash_PLCb_minus_Ca_minus_Gq_cplx

569151
type: LocalParameter
units: 424878
value: 7.2E-14

430182
type: SpeciesReference
stoichiometry: 1.0
species: 401157

430169
type: SpeciesReference
stoichiometry: 1.0
species: 401077

401077
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.73
initial amount: NaN
in compartment: 400538

430157
type: SpeciesReference
stoichiometry: 1.0
species: 400638

400638
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

430145
type: SpeciesReference
stoichiometry: 1.0
species: 401177

404257
type: Species
constant: true
boundary condition: true
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 400538

406557
type: Reaction
kinetic law: 429928
product: 429916
reactant: 429904
reactant: 429892
notes: See Porfiri and McCormick JBC 271:10 pp5871 1996 for the existence of this step. We\'ll take the rates from the ones used for the phosph of Raf by MAPK. Sep 17 1997: The transient activation curve matches better with k1 up by 10 x.
fast: false
reversible: true

429928
type: KineticLaw
local parameters: 569141
local parameters: 569140
notes: k1*Sos_slash_Sos*MAPK_star_-k2*MAPK_star__slash_phosph_Sos_slash_phosph_Sos_cplx

569141
type: LocalParameter
units: 424878
value: 6.0E-14

569140
type: LocalParameter
units: 424962
value: 2.925045E-14

429916
type: SpeciesReference
stoichiometry: 1.0
species: 401057

401057
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

429904
type: SpeciesReference
stoichiometry: 1.0
species: 400997

400997
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

429892
type: SpeciesReference
stoichiometry: 1.0
species: 402497

402497
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.1
initial amount: NaN
in compartment: 400538

407677
type: Reaction
kinetic law: 432693
product: 432681
reactant: 432669
reactant: 432657
fast: false
reversible: true

432693
type: KineticLaw
local parameters: 569252
local parameters: 569251
notes: k1*CaMKII_slash_CaMKII_minus_CaM*CaMKII_slash_tot_CaM_CaMKII-k2*CaMKII_slash_tot_CaM_CaMKII_slash_CaM_act_286_slash_CaM_act_286_cplx

569252
type: LocalParameter
units: 424878
value: 3.0E-15

569251
type: LocalParameter
units: 424962
value: 3.30102E-17

432681
type: SpeciesReference
stoichiometry: 1.0
species: 402737

432669
type: SpeciesReference
stoichiometry: 1.0
species: 404317

432657
type: SpeciesReference
stoichiometry: 1.0
species: 402617

402617
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

402437
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 400538

405617
type: Reaction
kinetic law: 427699
product: 427686
reactant: 427674
reactant: 427662
fast: false
reversible: true

427699
type: KineticLaw
local parameters: 569006
local parameters: 569003
notes: kf*CaM_minus_Ca3*CaNAB_minus_Ca4-kb*PP2B_slash_CaMCa3_minus_CaNAB

569006
type: LocalParameter
units: 424878
value: 1.5E-15

569003
type: LocalParameter
units: 424962
value: 3.357045E-15

427686
type: SpeciesReference
stoichiometry: 1.0
species: 403317

403317
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427674
type: SpeciesReference
stoichiometry: 1.0
species: 403237

427662
type: SpeciesReference
stoichiometry: 1.0
species: 402997

404837
type: Reaction
kinetic law: 425926
product: 425914
reactant: 425901
reactant: 425889
notes: kf = kf from text = 1e7 / M / sec = 10 /uM/sec = 10 / 6e5 / # / sec = 1.67e-5 kb = kr from text = 60 / sec Note that we continue to use uM here since [phenylephrine] is also in uM. From Martin et al FEBS Lett 316:2 191-196 1993 we have Kd = 600 nM Assuming kb = 10/sec, we get kf = 10/(0.6 uM * 6e5) = 2.8e-5 1/sec/#
fast: false
reversible: true

425926
type: KineticLaw
local parameters: 568854
local parameters: 568851
notes: kf*Gq_slash_mGluR*Glu-kb*Gq_slash_Rec_minus_Glu

568854
type: LocalParameter
units: 424878
value: 1.5E-14

568851
type: LocalParameter
units: 424962
value: 2.520045E-14

425914
type: SpeciesReference
stoichiometry: 1.0
species: 401317

401317
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

425901
type: SpeciesReference
stoichiometry: 1.0
species: 404117

425889
type: SpeciesReference
stoichiometry: 1.0
species: 401297

401297
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.3
initial amount: NaN
in compartment: 400538

404157
type: Species
notes: Phosphatidylcholine is the main (around 55%) metabolic product of DAG, follwed by PE (around 25%). Ref is Welsh and Cabot, JCB35:231-245(1987)
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400557

407017
type: Reaction
kinetic law: 431077
product: 431065
product: 431052
reactant: 431039
fast: false
reversible: false

431077
type: KineticLaw
local parameters: 569184
notes: k3*MKP_minus_1_slash_MKP1_minus_thr_minus_deph_slash_MKP1_minus_thr_minus_deph_cplx

569184
type: LocalParameter
units: 424878
value: 6.0E-15

431065
type: SpeciesReference
stoichiometry: 1.0
species: 401717

431052
type: SpeciesReference
stoichiometry: 1.0
species: 401497

431039
type: SpeciesReference
stoichiometry: 1.0
species: 401757

401757
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

401957
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

404677
type: Reaction
kinetic law: 425557
product: 425545
reactant: 425533
fast: false
reversible: true

425557
type: KineticLaw
local parameters: 568822
local parameters: 568819
notes: kf*PLA2_slash_PLA2_star_-kb*PLA2_slash_PLA2_minus_cytosolic

568822
type: LocalParameter
units: 424878
value: 0.0

568819
type: LocalParameter
units: 424878
value: 2.55E-16

425545
type: SpeciesReference
stoichiometry: 1.0
species: 400757

425533
type: SpeciesReference
stoichiometry: 1.0
species: 400977

400977
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405057
type: Reaction
kinetic law: 426448
product: 426436
reactant: 426424
fast: false
reversible: true

426448
type: KineticLaw
local parameters: 568898
local parameters: 568895
notes: kf*Ras_slash_GEF_star_-kb*Ras_slash_inact_minus_GEF

568898
type: LocalParameter
units: 424878
value: 0.0

568895
type: LocalParameter
units: 424878
value: 1.5E-15

426436
type: SpeciesReference
stoichiometry: 1.0
species: 401917

426424
type: SpeciesReference
stoichiometry: 1.0
species: 401937

400837
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405597
type: Reaction
kinetic law: 427650
product: 427638
reactant: 427626
reactant: 427614
notes: Disabled. See notes for PP2B7.g
fast: false
reversible: true

427650
type: KineticLaw
local parameters: 569002
local parameters: 568999
notes: kf*CaNAB_minus_Ca4*CaM_minus_TR2_minus_Ca2-kb*PP2B_slash_CaMCa2_minus_CANAB

569002
type: LocalParameter
units: 424878
value: 1.5E-15

568999
type: LocalParameter
units: 424962
value: 3.600045E-16

427638
type: SpeciesReference
stoichiometry: 1.0
species: 403337

403337
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

427626
type: SpeciesReference
stoichiometry: 1.0
species: 403017

427614
type: SpeciesReference
stoichiometry: 1.0
species: 403237

408217
type: Reaction
kinetic law: 434000
modifier: 433988
product: 433976
reactant: 433963
notes: Reduced Km to match expt data for basal activation of AC2 by PKC. Now k1 = 2.9e-6, k2 = 72, k3 = 18
fast: false
reversible: false

434000
type: KineticLaw
local parameters: 569307
local parameters: 569304
notes: kcat*AC_slash_AC2_star_*AC_slash_ATP/(Km+AC_slash_ATP)

569307
type: LocalParameter
units: 424842
value: 20.1152893440692

569304
type: LocalParameter
units: 424878
value: 1.05E-14

433976
type: SpeciesReference
stoichiometry: 1.0
species: 403557

433963
type: SpeciesReference
stoichiometry: 1.0
species: 404237

406357
type: Reaction
kinetic law: 429443
product: 429431
reactant: 429419
reactant: 429407
notes: 10 x raise oct 22 12 x and rescale for k2 = 4 * k3 convention oct 24 Increase further to get the match to expt, which was spoilt due to large accumulation of PLA2 in the enzyme complexed forms. Lets raise k3, leaving the others at k1 = 1.5e-5 and k2 = 144 since they are large already.
fast: false
reversible: true

429443
type: KineticLaw
local parameters: 569120
local parameters: 569119
notes: k1*PLA2_slash_APC*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star_-k2*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

569120
type: LocalParameter
units: 424878
value: 2.16E-13

569119
type: LocalParameter
units: 424962
value: 1.35E-14

429431
type: SpeciesReference
stoichiometry: 1.0
species: 400877

429419
type: SpeciesReference
stoichiometry: 1.0
species: 400857

429407
type: SpeciesReference
stoichiometry: 1.0
species: 404077

408037
type: Reaction
kinetic law: 433563
product: 433551
reactant: 433539
reactant: 433527
fast: false
reversible: true

433563
type: KineticLaw
local parameters: 569288
local parameters: 569285
notes: k1*PP1_slash_PP1_minus_I1_star_*CaM_po_Ca_pc_n_minus_CaNAB-k2*CaM_po_Ca_pc_n_minus_CaNAB_slash_dephosph_minus_PP1_minus_I_star__slash_dephosph_minus_PP1_minus_I_star__cplx

569288
type: LocalParameter
units: 424878
value: 2.04E-15

569285
type: LocalParameter
units: 424962
value: 5.13E-16

433551
type: SpeciesReference
stoichiometry: 1.0
species: 403077

433539
type: SpeciesReference
stoichiometry: 1.0
species: 404357

433527
type: SpeciesReference
stoichiometry: 1.0
species: 403137

408377
type: Reaction
kinetic law: 434386
product: 434374
reactant: 434361
reactant: 434349
notes: Rate is 1/6 of the CaM stim form. We\'ll just reduce all lf k1, k2, k3 so that the Vmax goes down 1/6.
fast: false
reversible: true

434386
type: KineticLaw
local parameters: 569329
local parameters: 569328
notes: k1*cAMP*AC_slash_PDE1-k2*AC_slash_PDE1_slash_PDE1_slash_PDE1_cplx

569329
type: LocalParameter
units: 424878
value: 1.0005E-14

569328
type: LocalParameter
units: 424962
value: 3.149955E-16

434374
type: SpeciesReference
stoichiometry: 1.0
species: 403837

434361
type: SpeciesReference
stoichiometry: 1.0
species: 403817

434349
type: SpeciesReference
stoichiometry: 1.0
species: 403557

407997
type: Reaction
kinetic law: 433467
product: 433455
reactant: 433443
reactant: 433431
fast: false
reversible: true

433467
type: KineticLaw
local parameters: 569282
local parameters: 569281
notes: k1*PP1_slash_I1_star_*CaM_po_Ca_pc_n_minus_CaNAB-k2*CaM_po_Ca_pc_n_minus_CaNAB_slash_dephosph_inhib1_slash_dephosph_inhib1_cplx

569282
type: LocalParameter
units: 424878
value: 2.04E-15

569281
type: LocalParameter
units: 424962
value: 5.13E-16

433455
type: SpeciesReference
stoichiometry: 1.0
species: 403057

403057
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

433443
type: SpeciesReference
stoichiometry: 1.0
species: 404357

433431
type: SpeciesReference
stoichiometry: 1.0
species: 403117

400617
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.161E-16
initial amount: NaN
in compartment: 400538

406257
type: Reaction
kinetic law: 429201
product: 429188
product: 429176
reactant: 429164
fast: false
reversible: false

429201
type: KineticLaw
local parameters: 569109
notes: k3*PKC_minus_active_slash_phosph_minus_AC2_slash_phosph_minus_AC2_cplx

569109
type: LocalParameter
units: 424878
value: 6.0E-15

429188
type: SpeciesReference
stoichiometry: 1.0
species: 404297

429176
type: SpeciesReference
stoichiometry: 1.0
species: 403617

429164
type: SpeciesReference
stoichiometry: 1.0
species: 400737

400737
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

402457
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

400897
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

404817
type: Reaction
kinetic law: 425877
product: 425865
reactant: 425853
reactant: 425840
notes: this step has a high affinity for Ca, from Smrcka et al. 0.1uM so kf /kb = 1/6e4 = 1.666e-5:1. See the Act-PLC-by-Gq reac. 11 Jun 1996: Raised kf to 5e-5 based on match to conc-eff curves from Smrcka et al.
fast: false
reversible: true

425877
type: KineticLaw
local parameters: 568850
local parameters: 568847
notes: kf*Ca*PLCbeta_slash_PLC_minus_Gq-kb*PLCbeta_slash_PLC_minus_Ca_minus_Gq

568850
type: LocalParameter
units: 424878
value: 1.5E-15

568847
type: LocalParameter
units: 424962
value: 4.499955E-14

425865
type: SpeciesReference
stoichiometry: 1.0
species: 401157

425853
type: SpeciesReference
stoichiometry: 1.0
species: 401197

401197
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

425840
type: SpeciesReference
stoichiometry: 1.0
species: 403917

407357
type: Reaction
kinetic law: 431897
product: 431884
reactant: 431872
reactant: 431860
notes: This pathway inhibits Ras when cAMP is elevated. See: Hordijk et al JBC 269:5 3534-3538 1994 Burgering et al EMBO J 12:11 4211-4220 1993 The rates are the same as used in PKA-phosph-I1
fast: false
reversible: true

431897
type: KineticLaw
local parameters: 569216
local parameters: 569215
notes: k1*Ras_slash_inact_minus_GEF*PKA_minus_active-k2*PKA_minus_active_slash_PKA_minus_phosph_minus_GEF_slash_PKA_minus_phosph_minus_GEF_cplx

569216
type: LocalParameter
units: 424878
value: 5.4E-14

569215
type: LocalParameter
units: 424962
value: 9.000045E-15

431884
type: SpeciesReference
stoichiometry: 1.0
species: 402157

431872
type: SpeciesReference
stoichiometry: 1.0
species: 402137

431860
type: SpeciesReference
stoichiometry: 1.0
species: 401917

400658
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407517
type: Reaction
kinetic law: 432284
product: 432272
reactant: 432260
reactant: 432248
notes: Hsu et al JBC 266:1 603-608 1991 Km = 385 +- 100 uM, Vm = 5.1 +-1 pmol/min/ug for PLC-771. Other sites have similar range, but are not stim as much by EGF. k1 = 2.8e-2/385/6e5 = 1.2e-10. Phenomenally slow. But Sherrill and Kyte say turnover # for angiotensin II is 5/min for cell extt, and 2/min for placental. Also see Okada et al for Shc rates which are much faster.
fast: false
reversible: true

432284
type: KineticLaw
local parameters: 569232
local parameters: 569231
notes: k1*PLC_g_slash_Ca_dot_PLC_g*EGFR_slash_L_dot_EGFR-k2*EGFR_slash_L_dot_EGFR_slash_phosph_PLC_g_slash_phosph_PLC_g_cplx

569232
type: LocalParameter
units: 424878
value: 1.2E-15

569231
type: LocalParameter
units: 424962
value: 4.499955E-15

432272
type: SpeciesReference
stoichiometry: 1.0
species: 402317

402317
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

432260
type: SpeciesReference
stoichiometry: 1.0
species: 402297

432248
type: SpeciesReference
stoichiometry: 1.0
species: 402557

407157
type: Reaction
kinetic law: 431414
product: 431402
reactant: 431390
reactant: 431378
notes: Ueki et al JBC 269(22) pp 15756-15761 1994 show hyperphosphorylation of craf, so this is there to dephosphorylate it. Identity of phosphatase is not known to me, but it may be PP2A like the rest, so I have made it so.
fast: false
reversible: true

569198
type: LocalParameter
units: 424878
value: 3.6E-14

569197
type: LocalParameter
units: 424962
value: 2.87415E-15

431402
type: SpeciesReference
stoichiometry: 1.0
species: 401857

431390
type: SpeciesReference
stoichiometry: 1.0
species: 401777

431378
type: SpeciesReference
stoichiometry: 1.0
species: 401477

401477
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

404657
type: Reaction
kinetic law: 425521
product: 425509
reactant: 425497
reactant: 425485
notes: To start off, same kinetics as the PLA2-Ca-act direct pathway. Oops ! Missed out the Ca input to this pathway first time round. Let\'s raise the forward rate about 3x to 5e-6. This will let us reduce the rather high rates we have used for the kenz on PLA2*-Ca. In fact, it may be that the rates are not that different, just that this pathway for getting the PLA2 to the memb is more efficien....
fast: false
reversible: true

425521
type: KineticLaw
local parameters: 568818
local parameters: 568815
notes: kf*PLA2_slash_PLA2_star_*Ca-kb*PLA2_slash_PLA2_star__minus_Ca

568818
type: LocalParameter
units: 424878
value: 1.5E-16

568815
type: LocalParameter
units: 424962
value: 9.000045E-15

425509
type: SpeciesReference
stoichiometry: 1.0
species: 400937

425497
type: SpeciesReference
stoichiometry: 1.0
species: 403917

425485
type: SpeciesReference
stoichiometry: 1.0
species: 400977

402717
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407337
type: Reaction
kinetic law: 431848
product: 431836
product: 431824
reactant: 431812
fast: false
reversible: false

431848
type: KineticLaw
local parameters: 569214
notes: k3*Ras_slash_CaM_minus_GEF_slash_CaM_minus_GEF_minus_act_minus_ras_slash_CaM_minus_GEF_minus_act_minus_ras_cplx

569214
type: LocalParameter
units: 424878
value: 3.0E-17

431836
type: SpeciesReference
stoichiometry: 1.0
species: 402097

402097
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

431824
type: SpeciesReference
stoichiometry: 1.0
species: 401977

431812
type: SpeciesReference
stoichiometry: 1.0
species: 402117

404737
type: Reaction
kinetic law: 425679
product: 425666
reactant: 425654
notes: These rates are the same as for degrading IP3, but I am sure that they could be improved. Lets double kf to 0.2, since the amount of DAG in the cell should be <= 1uM. Need to double it again, for the same reason. kf now 0.5 27 June 1996 kf is now 0.02 to get 50 sec time course 30 Aug 1997: Raised kf to 0.11 to accomodate PLC_gamma 27 Mar 1998: kf now 0.15 for PLC_gamma
fast: false
reversible: true

425679
type: KineticLaw
local parameters: 568834
local parameters: 568831
notes: kf*DAG-kb*PLCbeta_slash_PC

568834
type: LocalParameter
units: 424878
value: 0.0

568831
type: LocalParameter
units: 424878
value: 2.25E-16

425666
type: SpeciesReference
stoichiometry: 1.0
species: 404157

425654
type: SpeciesReference
stoichiometry: 1.0
species: 400638

406737
type: Reaction
kinetic law: 430388
product: 430376
product: 430363
reactant: 430351
fast: false
reversible: false

430388
type: KineticLaw
local parameters: 569157
notes: k3*MAPK_slash_MAPKK_star__slash_MAPKKthr_slash_MAPKKthr_cplx

569157
type: LocalParameter
units: 424878
value: 4.5E-16

430376
type: SpeciesReference
stoichiometry: 1.0
species: 401517

430363
type: SpeciesReference
stoichiometry: 1.0
species: 400997

430351
type: SpeciesReference
stoichiometry: 1.0
species: 401557

405357
type: Reaction
kinetic law: 427093
product: 427081
reactant: 427069
reactant: 427057
notes: This is tricky. There is some cooperativity here arising from interactions between the subunits of the CAMKII holoenzyme. However, the stoichiometry is 1. Kb/Kf = 6e4 #/cell. Rate is fast (see Hanson et al Neuron 12 943-956 1994) so lets say kb = 10. This gives kf = 1.6667e-4 H&S AnnRev Biochem 92 give tau for dissoc as 0.2 sec at low Ca, 0.4 at high. Low Ca = 100 nM = physiol.
fast: false
reversible: true

427093
type: KineticLaw
local parameters: 568954
local parameters: 568951
notes: kf*CaM_minus_Ca4*CaMKII_slash_CaMKII-kb*CaMKII_slash_CaMKII_minus_CaM

568954
type: LocalParameter
units: 424878
value: 7.5E-15

568951
type: LocalParameter
units: 424962
value: 7.499925E-14

427081
type: SpeciesReference
stoichiometry: 1.0
species: 402617

427069
type: SpeciesReference
stoichiometry: 1.0
species: 402597

427057
type: SpeciesReference
stoichiometry: 1.0
species: 402217

406037
type: Reaction
kinetic law: 428656
product: 428644
reactant: 428632
reactant: 428620
notes: Rate consts from Chen et al Biochem 32, 1032 (1993) k3 = k2 = 4 k1 = 9e-5 recalculated gives 1.666e-5, which is not very different. Looks like k3 is rate-limiting in this case: there is a huge amount of craf locked up in the enz complex. Let us assume a 10x higher Km, ie, lower affinity. k1 drops by 10x. Also changed k2 to 4x k3. Lowerd k1 to 1e-6 to balance 10X DAG sensitivity of PKC
fast: false
reversible: true

428656
type: KineticLaw
local parameters: 569090
local parameters: 569087
notes: k1*MAPK_slash_craf_minus_1*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_act_minus_raf_slash_PKC_minus_act_minus_raf_cplx

569090
type: LocalParameter
units: 424878
value: 2.4E-14

569087
type: LocalParameter
units: 424962
value: 1.499985E-15

428644
type: SpeciesReference
stoichiometry: 1.0
species: 400658

428632
type: SpeciesReference
stoichiometry: 1.0
species: 404297

428620
type: SpeciesReference
stoichiometry: 1.0
species: 401397

405037
type: Reaction
kinetic law: 426412
product: 426400
reactant: 426388
reactant: 426375
notes: SoS/GEF is present at 50 nM ie 3e4/cell. BetaGamma maxes out at 9e4. Assume we have 1/3 of the GEF active when the BetaGamma is 1.5e4. so 1e4 * kb = 2e4 * 1.5e4 * kf, so kf/kb = 3e-5. The rate of this equil should be reasonably fast, say 1/sec
fast: false
reversible: true

426412
type: KineticLaw
local parameters: 568894
local parameters: 568891
notes: kf*BetaGamma*Ras_slash_inact_minus_GEF-kb*Ras_slash_GEF_minus_Gprot_minus_bg

568894
type: LocalParameter
units: 424878
value: 1.5E-15

568891
type: LocalParameter
units: 424962
value: 9.000045E-15

426400
type: SpeciesReference
stoichiometry: 1.0
species: 401877

426388
type: SpeciesReference
stoichiometry: 1.0
species: 401917

426375
type: SpeciesReference
stoichiometry: 1.0
species: 401217

404497
type: Reaction
kinetic law: 425157
product: 425145
reactant: 425133
fast: false
reversible: true

425157
type: KineticLaw
local parameters: 568790
local parameters: 568789
notes: kf*PKC_slash_PKC_minus_Ca-kb*PKC_slash_PKC_minus_Ca_minus_memb_star_

568790
type: LocalParameter
units: 424878
value: 5.2539E-15

568789
type: LocalParameter
units: 424878
value: 1.90575E-15

425145
type: SpeciesReference
stoichiometry: 1.0
species: 400578

400578
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.38955555555556E-17
initial amount: NaN
in compartment: 400538

425133
type: SpeciesReference
stoichiometry: 1.0
species: 400558

408077
type: Reaction
kinetic law: 433659
product: 433647
reactant: 433635
reactant: 433623
notes: PP2A does most of the dephosph of I1 at basal Ca levels. See the review by Cohen in Ann Rev Biochem 1989. For now, lets halve Km. k1 was 3.3e-6, now 6.6e-6
fast: false
reversible: true

433659
type: KineticLaw
local parameters: 569291
local parameters: 569290
notes: k1*PP1_slash_I1_star_*PP2A-k2*PP2A_slash_PP2A_minus_dephosph_minus_I1_slash_PP2A_minus_dephosph_minus_I1_cplx

569291
type: LocalParameter
units: 424878
value: 3.75E-14

569290
type: LocalParameter
units: 424962
value: 5.94E-15

433647
type: SpeciesReference
stoichiometry: 1.0
species: 403197

433635
type: SpeciesReference
stoichiometry: 1.0
species: 403177

433623
type: SpeciesReference
stoichiometry: 1.0
species: 403117

405197
type: Reaction
kinetic law: 426728
product: 426716
reactant: 426704
notes: See Helin and Beguinot JBC 266:13 1991 pg 8363-8368. In Fig 3 they have internalization tau about 10 min, equil at about 20% EGF available. So kf = 4x kb, and 1/(kf + kb) = 600 sec so kb = 1/3K = 3.3e-4, and kf = 1.33e-3. This doesn\'t take into account the unbound receptor, so we need to push the kf up a bit, to 0.002
fast: false
reversible: true

426728
type: KineticLaw
local parameters: 568926
local parameters: 568923
notes: kf*EGFR_slash_L_dot_EGFR-kb*EGFR_slash_Internal_L_dot_EGFR

568926
type: LocalParameter
units: 424878
value: 4.95E-19

568923
type: LocalParameter
units: 424878
value: 3.0E-18

426716
type: SpeciesReference
stoichiometry: 1.0
species: 402397

426704
type: SpeciesReference
stoichiometry: 1.0
species: 402297

406897
type: Reaction
kinetic law: 430776
product: 430764
product: 430751
reactant: 430738
fast: false
reversible: false

430776
type: KineticLaw
local parameters: 569172
notes: k3*MAPK_slash_Raf_star__minus_GTP_minus_Ras_slash_Raf_star__minus_GTP_minus_Ras_dot_1_slash_Raf_star__minus_GTP_minus_Ras_dot_1_cplx

569172
type: LocalParameter
units: 424878
value: 4.5E-16

430764
type: SpeciesReference
stoichiometry: 1.0
species: 401657

430751
type: SpeciesReference
stoichiometry: 1.0
species: 401577

430738
type: SpeciesReference
stoichiometry: 1.0
species: 401677

401677
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407837
type: Reaction
kinetic law: 433080
product: 433068
reactant: 433056
reactant: 433044
notes: See Cohen et al
fast: false
reversible: true

433080
type: KineticLaw
local parameters: 569267
local parameters: 569266
notes: k1*CaMKII_slash_CaMK_minus_thr306*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr306_slash_Deph_minus_thr306_cplx

569267
type: LocalParameter
units: 424878
value: 2.1E-15

569266
type: LocalParameter
units: 424962
value: 5.147955E-16

433068
type: SpeciesReference
stoichiometry: 1.0
species: 402857

433056
type: SpeciesReference
stoichiometry: 1.0
species: 402797

433044
type: SpeciesReference
stoichiometry: 1.0
species: 402697

402697
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407097
type: Reaction
kinetic law: 431270
product: 431258
product: 431246
reactant: 431234
fast: false
reversible: false

569193
type: LocalParameter
units: 424878
value: 9.0E-15

431258
type: SpeciesReference
stoichiometry: 1.0
species: 401777

431246
type: SpeciesReference
stoichiometry: 1.0
species: 401577

431234
type: SpeciesReference
stoichiometry: 1.0
species: 401817

404597
type: Reaction
kinetic law: 425389
product: 425377
reactant: 425364
reactant: 425352
fast: false
reversible: true

425389
type: KineticLaw
local parameters: 568806
local parameters: 568803
notes: kf*temp_minus_PIP2*PLA2_slash_PLA2_minus_Ca_star_-kb*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star_

568806
type: LocalParameter
units: 424878
value: 1.5E-16

568803
type: LocalParameter
units: 424962
value: 1.799955E-17

425377
type: SpeciesReference
stoichiometry: 1.0
species: 400857

425364
type: SpeciesReference
stoichiometry: 1.0
species: 400777

425352
type: SpeciesReference
stoichiometry: 1.0
species: 404097

405277
type: Reaction
kinetic law: 426910
product: 426898
reactant: 426886
reactant: 426874
notes: As there are 2 SH3 domains, this reaction could be 2nd order. I have a Kd of 22 uM from peptide binding (Lemmon et al JBC 269:50 pg 31653). However, Chook et al JBC 271:48 pg30472 say it is 0.4uM with purified proteins, so we believe them. They say it is 1:1 binding.
fast: false
reversible: true

426910
type: KineticLaw
local parameters: 568942
local parameters: 568939
notes: kf*Sos_slash_Grb2*Sos_slash_Sos-kb*Sos_slash_Sos_dot_Grb2

568942
type: LocalParameter
units: 424878
value: 2.52E-17

568939
type: LocalParameter
units: 424962
value: 3.75003E-17

426898
type: SpeciesReference
stoichiometry: 1.0
species: 402457

426886
type: SpeciesReference
stoichiometry: 1.0
species: 402497

426874
type: SpeciesReference
stoichiometry: 1.0
species: 402437

406997
type: Reaction
kinetic law: 431027
product: 431015
reactant: 431003
reactant: 430990
notes: See MKP1-tyr-deph
fast: false
reversible: true

431027
type: KineticLaw
local parameters: 569183
local parameters: 569182
notes: k1*MAPK_star_*MKP_minus_1-k2*MKP_minus_1_slash_MKP1_minus_thr_minus_deph_slash_MKP1_minus_thr_minus_deph_cplx

569183
type: LocalParameter
units: 424878
value: 2.4E-14

569182
type: LocalParameter
units: 424962
value: 4.28571E-15

431015
type: SpeciesReference
stoichiometry: 1.0
species: 401757

431003
type: SpeciesReference
stoichiometry: 1.0
species: 401717

430990
type: SpeciesReference
stoichiometry: 1.0
species: 400997

405317
type: Reaction
kinetic law: 427008
product: 426996
reactant: 426983
reactant: 426970
notes: Again, we refer to Homma et al and Wahl et al, for preference using Wahl. Half-Max of the phosph form is at 316 nM. Use kb of 10 as this is likely to be pretty fast. Did some curve comparisons, and instead of 316 nM giving a kf of 5.27e-5, we will use 8e-5 for kf. 16 Sep 97. As we are now phosphorylating the Ca-bound form, equils have shifted. kf should now be 2e-5 to match the curves.
fast: false
reversible: true

427008
type: KineticLaw
local parameters: 568948
local parameters: 568947
notes: kf*Ca*PLC_g_slash_PLC_G_star_-kb*PLC_g_slash_Ca_dot_PLC_g_star_

568948
type: LocalParameter
units: 424878
value: 1.5E-14

568947
type: LocalParameter
units: 424962
value: 1.799955E-14

426996
type: SpeciesReference
stoichiometry: 1.0
species: 402577

402577
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426983
type: SpeciesReference
stoichiometry: 1.0
species: 402537

402537
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

426970
type: SpeciesReference
stoichiometry: 1.0
species: 403917

407757
type: Reaction
kinetic law: 432888
product: 432875
reactant: 432863
reactant: 432851
fast: false
reversible: true

432888
type: KineticLaw
local parameters: 569261
local parameters: 569258
notes: k1*CaMKII_slash_CaMKII_minus_CaM*CaMKII_slash_tot_autonomous_CaMKII-k2*CaMKII_slash_tot_autonomous_CaMKII_slash_auton_286_slash_auton_286_cplx

569261
type: LocalParameter
units: 424878
value: 3.0E-15

569258
type: LocalParameter
units: 424962
value: 2.142855E-17

432875
type: SpeciesReference
stoichiometry: 1.0
species: 402777

432863
type: SpeciesReference
stoichiometry: 1.0
species: 404337

432851
type: SpeciesReference
stoichiometry: 1.0
species: 402617

407117
type: Reaction
kinetic law: 431318
product: 431306
reactant: 431294
reactant: 431282
fast: false
reversible: true

569195
type: LocalParameter
units: 424878
value: 3.6E-14

569194
type: LocalParameter
units: 424962
value: 2.87415E-15

431306
type: SpeciesReference
stoichiometry: 1.0
species: 401837

431294
type: SpeciesReference
stoichiometry: 1.0
species: 401777

431282
type: SpeciesReference
stoichiometry: 1.0
species: 401577

404757
type: Reaction
kinetic law: 425728
product: 425715
reactant: 425703
reactant: 425691
notes: Affinity for Gq is > 20 nM (Smrcka et al Science251 804-807 1991) so [Gq].kf = kb so 40nM * 6e5 = kb/kf = 24e3 so kf = 4.2e-5, kb =1
fast: false
reversible: true

425728
type: KineticLaw
local parameters: 568838
local parameters: 568835
notes: kf*G_star_GTP*PLCbeta_slash_PLC_minus_Ca-kb*PLCbeta_slash_PLC_minus_Ca_minus_Gq

568838
type: LocalParameter
units: 424878
value: 1.5E-15

568835
type: LocalParameter
units: 424962
value: 3.78E-14

425715
type: SpeciesReference
stoichiometry: 1.0
species: 401157

425703
type: SpeciesReference
stoichiometry: 1.0
species: 401117

425691
type: SpeciesReference
stoichiometry: 1.0
species: 401237

406837
type: Reaction
kinetic law: 430630
product: 430618
reactant: 430606
reactant: 430594
notes: Kinetics are the same as for the craf_1* activity, ie., k1=5.5e-6, k2=0.42, k3 = 0.105 These are basedo n Force et al PNAS USA 91 1270-1274, 1994., but k1 is scaled up 5x (ie., Km is scaled down 5x to the value used here and for craf_1* activity: Km = 0.1591).
fast: false
reversible: true

430630
type: KineticLaw
local parameters: 569168
local parameters: 569167
notes: k1*MAPK_slash_MAPKK_minus_ser*MAPK_slash_Raf_minus_GTP_minus_Ras-k2*MAPK_slash_Raf_minus_GTP_minus_Ras_slash_Raf_minus_GTP_minus_Ras_dot_2_slash_Raf_minus_GTP_minus_Ras_dot_2_cplx

569168
type: LocalParameter
units: 424878
value: 1.8E-15

569167
type: LocalParameter
units: 424962
value: 1.41426E-14

430618
type: SpeciesReference
stoichiometry: 1.0
species: 401637

430606
type: SpeciesReference
stoichiometry: 1.0
species: 401597

430594
type: SpeciesReference
stoichiometry: 1.0
species: 401577

406417
type: Reaction
kinetic law: 429589
product: 429576
product: 429564
reactant: 429552
fast: false
reversible: false

429589
type: KineticLaw
local parameters: 569127
notes: k3*PLA2_slash_DAG_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

569127
type: LocalParameter
units: 424878
value: 9.0E-14

429576
type: SpeciesReference
stoichiometry: 1.0
species: 400897

429564
type: SpeciesReference
stoichiometry: 1.0
species: 400657

429552
type: SpeciesReference
stoichiometry: 1.0
species: 400917

407437
type: Reaction
kinetic law: 432091
product: 432079
reactant: 432067
reactant: 432055
notes: Same rates as PKA-phosph-I1
fast: false
reversible: true

432091
type: KineticLaw
local parameters: 569226
local parameters: 569223
notes: k1*AC_slash_cAMP_minus_PDE*PKA_minus_active-k2*PKA_minus_active_slash_phosph_minus_PDE_slash_phosph_minus_PDE_cplx

569226
type: LocalParameter
units: 424878
value: 5.4E-14

569223
type: LocalParameter
units: 424962
value: 9.000045E-15

432079
type: SpeciesReference
stoichiometry: 1.0
species: 402197

432067
type: SpeciesReference
stoichiometry: 1.0
species: 402137

432055
type: SpeciesReference
stoichiometry: 1.0
species: 403737

403737
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.45
initial amount: NaN
in compartment: 400538

406057
type: Reaction
kinetic law: 428704
product: 428692
product: 428680
reactant: 428668
fast: false
reversible: false

428704
type: KineticLaw
local parameters: 569091
notes: k3*PKC_minus_active_slash_PKC_minus_act_minus_raf_slash_PKC_minus_act_minus_raf_cplx

569091
type: LocalParameter
units: 424878
value: 6.0E-15

428692
type: SpeciesReference
stoichiometry: 1.0
species: 404297

428680
type: SpeciesReference
stoichiometry: 1.0
species: 401417

428668
type: SpeciesReference
stoichiometry: 1.0
species: 400658

406517
type: Reaction
kinetic law: 429831
product: 429819
reactant: 429807
reactant: 429795
notes: Ueki et al JBC 269(22):15756-15761 show the presence of this step, but not the rate consts, which are derived from Sanghera et al JBC 265(1):52-57, 1990, see the deriv in the MAPK* notes.
fast: false
reversible: true

429831
type: KineticLaw
local parameters: 569138
local parameters: 569135
notes: k1*MAPK_slash_craf_minus_1_star_*MAPK_star_-k2*MAPK_star__slash_MAPK_star__minus_feedback_slash_MAPK_star__minus_feedback_cplx

569138
type: LocalParameter
units: 424878
value: 6.0E-14

569135
type: LocalParameter
units: 424962
value: 2.925045E-15

429819
type: SpeciesReference
stoichiometry: 1.0
species: 401037

429807
type: SpeciesReference
stoichiometry: 1.0
species: 400997

429795
type: SpeciesReference
stoichiometry: 1.0
species: 401417

405137
type: Reaction
kinetic law: 426608
product: 426596
reactant: 426584
fast: false
reversible: true

426608
type: KineticLaw
local parameters: 568914
local parameters: 568911
notes: kf*Ras_slash_inact_minus_GEF_star_-kb*Ras_slash_inact_minus_GEF

568914
type: LocalParameter
units: 424878
value: 0.0

568911
type: LocalParameter
units: 424878
value: 1.5E-15

426596
type: SpeciesReference
stoichiometry: 1.0
species: 401917

426584
type: SpeciesReference
stoichiometry: 1.0
species: 402077

407597
type: Reaction
modifier: 432477
reversible: false
notes: Mainly Homma et al JBC 263:14 1988 pp 6592, but these parms are the Ca-stimulated form. It is not clear whether the enzyme is activated by tyrosine phosphorylation at this point or not. Wahl et al JBC 267:15 10447-10456 1992 say that the Ca_stim and phosph form has 7X higher affinity for substrate than control. This is close to Wahl\'s figure 7, which I am using as reference.
fast: false
reactant: 432440
product: 432452
product: 432465
kinetic law: 432489

432440
type: SpeciesReference
stoichiometry: 1.0
species: 404177

432452
type: SpeciesReference
stoichiometry: 1.0
species: 400638

432465
type: SpeciesReference
stoichiometry: 1.0
species: 401077

432489
type: KineticLaw
local parameters: 569241
local parameters: 569238
notes: kcat*PLC_g_slash_Ca_dot_PLC_g*PIP2/(Km+PIP2)

569241
type: LocalParameter
units: 424842
value: 97.2222222222222

569238
type: LocalParameter
units: 424878
value: 2.1E-14

400597
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 9.43511111111111E-21
initial amount: NaN
in compartment: 400538

407637
type: Reaction
kinetic law: 432597
product: 432585
reactant: 432573
reactant: 432561
notes: Rates from autocamtide phosphorylation, from Hanson and Schulman JBC 267:24 17216-17224 1992. Jan 1 1998: Speed up 12x to match fig 5.
fast: false
reversible: true

432597
type: KineticLaw
local parameters: 569249
local parameters: 569246
notes: k1*CaMKII_slash_CaMKII_minus_thr286*CaMKII_slash_tot_CaM_CaMKII-k2*CaMKII_slash_tot_CaM_CaMKII_slash_CaM_act_305_slash_CaM_act_305_cplx

569249
type: LocalParameter
units: 424878
value: 3.6E-14

569246
type: LocalParameter
units: 424962
value: 3.961305E-16

432585
type: SpeciesReference
stoichiometry: 1.0
species: 402717

432573
type: SpeciesReference
stoichiometry: 1.0
species: 404317

432561
type: SpeciesReference
stoichiometry: 1.0
species: 402677

403657
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.015
initial amount: NaN
in compartment: 400538

405337
type: Reaction
kinetic law: 427045
product: 427033
reactant: 427021
fast: false
reversible: true

427045
type: KineticLaw
local parameters: 568950
local parameters: 568949
notes: kf*PLC_g_slash_Ca_dot_PLC_g_star_-kb*PLC_g_slash_Ca_dot_PLC_g

568950
type: LocalParameter
units: 424878
value: 0.0

568949
type: LocalParameter
units: 424878
value: 7.5E-17

427033
type: SpeciesReference
stoichiometry: 1.0
species: 402557

427021
type: SpeciesReference
stoichiometry: 1.0
species: 402577

406237
type: Reaction
kinetic law: 429152
product: 429140
reactant: 429128
reactant: 429116
notes: Phorbol esters have little effect on AC1 or on the Gs-stimulation of AC2. So in this model we are only dealing with the increase in basal activation of AC2 induced by PKC k1 = 1.66e-6 k2 = 16 k3 =4
fast: false
reversible: true

429152
type: KineticLaw
local parameters: 569108
local parameters: 569107
notes: k1*AC_slash_AC2*PKC_minus_active-k2*PKC_minus_active_slash_phosph_minus_AC2_slash_phosph_minus_AC2_cplx

569108
type: LocalParameter
units: 424878
value: 2.4E-14

569107
type: LocalParameter
units: 424962
value: 9.000045E-16

429140
type: SpeciesReference
stoichiometry: 1.0
species: 400737

429128
type: SpeciesReference
stoichiometry: 1.0
species: 404297

429116
type: SpeciesReference
stoichiometry: 1.0
species: 403657

407277
type: Reaction
kinetic law: 431704
product: 431692
reactant: 431680
reactant: 431668
notes: From Eccleston et al JBC 268(36)pp27012-19 get Kd < 2uM, kcat - 10/sec From Martin et al Cell 63 843-849 1990 get Kd ~ 250 nM, kcat = 20/min I will go with the Eccleston figures as there are good error bars (10%). In general the values are reasonably close. k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting) 5 Nov 2002: Changed ratio term to 4 from 100. Now we have k1=8.25e-5; k2=40, k3=10. k3 is still rate-limiting.
fast: false
reversible: true

431704
type: KineticLaw
local parameters: 569210
local parameters: 569209
notes: k1*Ras_slash_GTP_minus_Ras*Ras_slash_GAP-k2*Ras_slash_GAP_slash_GAP_minus_inact_minus_ras_slash_GAP_minus_inact_minus_ras_cplx

569210
type: LocalParameter
units: 424878
value: 6.0E-14

569209
type: LocalParameter
units: 424962
value: 7.42284E-14

431692
type: SpeciesReference
stoichiometry: 1.0
species: 402057

431680
type: SpeciesReference
stoichiometry: 1.0
species: 402037

431668
type: SpeciesReference
stoichiometry: 1.0
species: 401977

406437
type: Reaction
kinetic law: 429638
product: 429626
reactant: 429614
reactant: 429601
notes: This form should be 3 to 6 times as fast as the Ca-only form. I have scaled by 4x which seems to give a 5x rise. 10x raise Oct 22 12 x oct 24, changed k2 = 4 * k3
fast: false
reversible: true

429638
type: KineticLaw
local parameters: 569129
local parameters: 569128
notes: k1*PLA2_slash_APC*PLA2_slash_PLA2_star__minus_Ca-k2*PLA2_slash_PLA2_star__minus_Ca_slash_kenz_slash_kenz_cplx

569129
type: LocalParameter
units: 424878
value: 7.2E-13

569128
type: LocalParameter
units: 424962
value: 4.499955E-14

429626
type: SpeciesReference
stoichiometry: 1.0
species: 400957

429614
type: SpeciesReference
stoichiometry: 1.0
species: 400937

429601
type: SpeciesReference
stoichiometry: 1.0
species: 404077

408297
type: Reaction
kinetic law: 434193
product: 434181
reactant: 434169
reactant: 434157
notes: Best rates are from Conti et al Biochem 34 7979-7987 1995. Though these are for the Sertoli cell form, it looks like they carry nicely into alternatively spliced brain form. See Sette et al JBC 269:28 18271-18274 Km ~2 uM, Vmax est ~ 10 umol/min/mg for pure form. Brain protein is 93 kD but this was 67. So k3 ~10, k2 ~40, k1 ~4.2e-6
fast: false
reversible: true

434193
type: KineticLaw
local parameters: 569323
local parameters: 569320
notes: k1*cAMP*AC_slash_cAMP_minus_PDE-k2*AC_slash_cAMP_minus_PDE_slash_PDE_slash_PDE_cplx

569323
type: LocalParameter
units: 424878
value: 6.0E-14

569320
type: LocalParameter
units: 424962
value: 3.78E-15

434181
type: SpeciesReference
stoichiometry: 1.0
species: 403757

403757
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

434169
type: SpeciesReference
stoichiometry: 1.0
species: 403737

434157
type: SpeciesReference
stoichiometry: 1.0
species: 403557

401017
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405797
type: Reaction
kinetic law: 428137
product: 428125
reactant: 428112
reactant: 428100
notes: Half-max at 20 nM CaM (Tang et al JBC 266:13 8595-8603 1991 kb/kf = 20 nM = 12000 #/cell so kf = kb/12000 = kb * 8.333e-5
fast: false
reversible: true

428137
type: KineticLaw
local parameters: 569042
local parameters: 569039
notes: kf*CaM_minus_Ca4*AC_slash_AC1-kb*AC_slash_AC1_minus_CaM

569042
type: LocalParameter
units: 424878
value: 1.5E-15

569039
type: LocalParameter
units: 424962
value: 7.499925E-14

428125
type: SpeciesReference
stoichiometry: 1.0
species: 403577

428112
type: SpeciesReference
stoichiometry: 1.0
species: 403597

428100
type: SpeciesReference
stoichiometry: 1.0
species: 402217

403277
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 400538

408457
type: Reaction
kinetic law: 434580
product: 434568
reactant: 434556
reactant: 434544
fast: false
reversible: true

434580
type: KineticLaw
local parameters: 569338
local parameters: 569335
notes: k1*PKM_slash_AA_pool*PKM_slash_PKM_synthesis-k2*PKM_slash_PKM_synthesis_slash_kenz_slash_kenz_cplx

569338
type: LocalParameter
units: 424878
value: 3.0E-16

569335
type: LocalParameter
units: 424962
value: 3.75003E-17

434568
type: SpeciesReference
stoichiometry: 1.0
species: 403997

434556
type: SpeciesReference
stoichiometry: 1.0
species: 403977

434544
type: SpeciesReference
stoichiometry: 1.0
species: 404257

407537
type: Reaction
kinetic law: 432332
product: 432320
product: 432308
reactant: 432296
fast: false
reversible: false

432332
type: KineticLaw
local parameters: 569233
notes: k3*EGFR_slash_L_dot_EGFR_slash_phosph_PLC_g_slash_phosph_PLC_g_cplx

569233
type: LocalParameter
units: 424878
value: 3.0E-16

432320
type: SpeciesReference
stoichiometry: 1.0
species: 402297

432308
type: SpeciesReference
stoichiometry: 1.0
species: 402577

432296
type: SpeciesReference
stoichiometry: 1.0
species: 402317

404537
type: Reaction
kinetic law: 425243
product: 425231
reactant: 425218
reactant: 425206
notes: kf raised 10 X based on Shinomura et al PNAS 88 5149-5153 1991 closer analysis of Shinomura et al: kf now 1e-8 (was 1.66e-8). Further tweak. To get sufficient AA synergy, increase kf to 1.5e-8 26 June 1996: Corrected DAG levels: reduce kf by 15x from 1.5e-8 to 1e-9
fast: false
reversible: true

425243
type: KineticLaw
local parameters: 568794
local parameters: 568793
notes: kf*PKC_slash_PKC_minus_cytosolic*DAG-kb*PKC_slash_PKC_minus_DAG

568794
type: LocalParameter
units: 424878
value: 1.5E-16

568793
type: LocalParameter
units: 424962
value: 9.000045E-19

425231
type: SpeciesReference
stoichiometry: 1.0
species: 400617

425218
type: SpeciesReference
stoichiometry: 1.0
species: 400638

425206
type: SpeciesReference
stoichiometry: 1.0
species: 400618

406597
type: Reaction
kinetic law: 430025
product: 430013
reactant: 430001
reactant: 429989
notes: From Sternweis et al Phil Trans R Soc Lond 1992, also matched by Homma et al. k1 = 1.5e-5, now 4.2e-6 k2 = 70/sec; now 40/sec k3 = 17.5/sec; now 10/sec Note that the wording in Sternweis et al is ambiguous re the Km.
fast: false
reversible: true

430025
type: KineticLaw
local parameters: 569144
local parameters: 569143
notes: k1*PIP2*PLCbeta_slash_PLC_minus_Ca-k2*PLCbeta_slash_PLC_minus_Ca_slash_PLC_minus_Ca_slash_PLC_minus_Ca_cplx

569144
type: LocalParameter
units: 424878
value: 6.0E-14

569143
type: LocalParameter
units: 424962
value: 3.78E-15

430013
type: SpeciesReference
stoichiometry: 1.0
species: 401137

430001
type: SpeciesReference
stoichiometry: 1.0
species: 401117

429989
type: SpeciesReference
stoichiometry: 1.0
species: 404177

406937
type: Reaction
kinetic law: 430881
product: 430868
product: 430855
reactant: 430841
fast: false
reversible: false

430881
type: KineticLaw
local parameters: 569178
notes: k3*MAPK_slash_Raf_star__minus_GTP_minus_Ras_slash_Raf_star__minus_GTP_minus_Ras_dot_2_slash_Raf_star__minus_GTP_minus_Ras_dot_2_cplx

569178
type: LocalParameter
units: 424878
value: 4.5E-16

430868
type: SpeciesReference
stoichiometry: 1.0
species: 401657

430855
type: SpeciesReference
stoichiometry: 1.0
species: 401517

430841
type: SpeciesReference
stoichiometry: 1.0
species: 401697

401697
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406797
type: Reaction
kinetic law: 430534
product: 430522
reactant: 430509
reactant: 430497
notes: Kinetics are the same as for the craf_1* activity, ie., k1=5.5e-6, k2=0.42, k3 = 0.105 These are basedo n Force et al PNAS USA 91 1270-1274, 1994., but k1 is scaled up 5x (ie., Km is scaled down 5x to the value used here and for craf_1* activity: Km = 0.1591).
fast: false
reversible: true

430534
type: KineticLaw
local parameters: 569165
local parameters: 569162
notes: k1*MAPK_slash_MAPKK*MAPK_slash_Raf_minus_GTP_minus_Ras-k2*MAPK_slash_Raf_minus_GTP_minus_Ras_slash_Raf_minus_GTP_minus_Ras_dot_1_slash_Raf_minus_GTP_minus_Ras_dot_1_cplx

569165
type: LocalParameter
units: 424878
value: 1.8E-15

569162
type: LocalParameter
units: 424962
value: 1.41426E-14

430522
type: SpeciesReference
stoichiometry: 1.0
species: 401617

430509
type: SpeciesReference
stoichiometry: 1.0
species: 401597

430497
type: SpeciesReference
stoichiometry: 1.0
species: 401437

401437
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.5
initial amount: NaN
in compartment: 400538

405817
type: Reaction
kinetic law: 428173
product: 428161
reactant: 428149
notes: Random rate.
fast: false
reversible: true

428173
type: KineticLaw
local parameters: 569046
local parameters: 569043
notes: kf*AC_slash_AC2_star_-kb*AC_slash_AC2

569046
type: LocalParameter
units: 424878
value: 0.0

569043
type: LocalParameter
units: 424878
value: 1.5E-16

428161
type: SpeciesReference
stoichiometry: 1.0
species: 403657

428149
type: SpeciesReference
stoichiometry: 1.0
species: 403617

404877
type: Reaction
kinetic law: 426024
product: 426012
reactant: 426000
reactant: 425987
notes: kf == kg3 = 1e-5 /cell/sec. As usual, there is no back-reaction kb = 0
fast: false
reversible: true

426024
type: KineticLaw
local parameters: 568862
local parameters: 568859
notes: kf*G_star_GDP*BetaGamma-kb*Gq_slash_G_minus_GDP

568862
type: LocalParameter
units: 424878
value: 0.0

568859
type: LocalParameter
units: 424962
value: 9.000045E-15

426012
type: SpeciesReference
stoichiometry: 1.0
species: 401277

426000
type: SpeciesReference
stoichiometry: 1.0
species: 401217

425987
type: SpeciesReference
stoichiometry: 1.0
species: 401257

407417
type: Reaction
kinetic law: 432043
product: 432031
product: 432019
reactant: 432007
fast: false
reversible: false

432043
type: KineticLaw
local parameters: 569222
notes: k3*PKA_minus_active_slash_PKA_minus_phosph_minus_I1_slash_PKA_minus_phosph_minus_I1_cplx

569222
type: LocalParameter
units: 424878
value: 1.35E-14

432031
type: SpeciesReference
stoichiometry: 1.0
species: 402137

432019
type: SpeciesReference
stoichiometry: 1.0
species: 403117

432007
type: SpeciesReference
stoichiometry: 1.0
species: 402177

406017
type: Reaction
kinetic law: 428608
product: 428596
reactant: 428584
fast: false
reversible: true

428608
type: KineticLaw
local parameters: 569086
local parameters: 569083
notes: kf*PKM_slash_PKM_synthesis-kb*PKM_slash_PKM_activator

569086
type: LocalParameter
units: 424878
value: 0.0

569083
type: LocalParameter
units: 424878
value: 1.5E-18

428596
type: SpeciesReference
stoichiometry: 1.0
species: 404057

404057
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0944444444444444
initial amount: NaN
in compartment: 400538

428584
type: SpeciesReference
stoichiometry: 1.0
species: 403977

404917
type: Reaction
kinetic law: 426110
product: 426097
reactant: 426085
reactant: 426073
notes: This is the k1-k2 equivalent for enzyme complex formation in the binding of Rec-Glu to Gq. See Fay et al Biochem 30 5066-5075 1991. kf = 5e-5 which is nearly the same as calculated by Fay et al. (4.67e-5) kb = .04 June 1996: Closer reading of Fay et al suggests that kb <= 0.0001, so kf = 1e-8 by detailed balance. This reaction appears to be neglible.
fast: false
reversible: true

426110
type: KineticLaw
local parameters: 568870
local parameters: 568867
notes: kf*Gq_slash_G_minus_GDP*Gq_slash_Rec_minus_Glu-kb*Gq_slash_Rec_minus_Glu_minus_Gq

568870
type: LocalParameter
units: 424878
value: 1.5E-19

568867
type: LocalParameter
units: 424962
value: 9.000045E-18

426097
type: SpeciesReference
stoichiometry: 1.0
species: 401357

426085
type: SpeciesReference
stoichiometry: 1.0
species: 401317

426073
type: SpeciesReference
stoichiometry: 1.0
species: 401277

407057
type: Reaction
kinetic law: 431174
product: 431162
product: 431150
reactant: 431138
fast: false
reversible: false

569187
type: LocalParameter
units: 424878
value: 9.0E-15

431162
type: SpeciesReference
stoichiometry: 1.0
species: 401777

431150
type: SpeciesReference
stoichiometry: 1.0
species: 401397

431138
type: SpeciesReference
stoichiometry: 1.0
species: 401797

408137
type: Reaction
kinetic law: 433806
product: 433793
product: 433781
reactant: 433769
fast: false
reversible: false

433806
type: KineticLaw
local parameters: 569295
notes: k3*PP2A_slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__cplx

569295
type: LocalParameter
units: 424878
value: 9.0E-15

433793
type: SpeciesReference
stoichiometry: 1.0
species: 403177

433781
type: SpeciesReference
stoichiometry: 1.0
species: 403157

433769
type: SpeciesReference
stoichiometry: 1.0
species: 403217

406497
type: Reaction
kinetic law: 429783
product: 429770
product: 429758
reactant: 429746
fast: false
reversible: false

429783
type: KineticLaw
local parameters: 569133
notes: k3*MAPK_star__slash_MAPK_star__slash_MAPK_star__cplx

569133
type: LocalParameter
units: 424878
value: 1.5E-14

429770
type: SpeciesReference
stoichiometry: 1.0
species: 400997

429758
type: SpeciesReference
stoichiometry: 1.0
species: 400977

429746
type: SpeciesReference
stoichiometry: 1.0
species: 401017

406117
type: Reaction
kinetic law: 428850
product: 428838
reactant: 428825
reactant: 428813
notes: Rate consts from PKC-act-raf. This reaction activates GEF. It can lead to at least 2X stim of ras, and a 2X stim of MAPK over and above that obtained via direct phosph of c-raf. Note that it is a push-pull reaction, and there is also a contribution through the phosphorylation and inactivation of GAPs. The original PKC-act-raf rate consts are too fast. We lower K1 by 10 X
fast: false
reversible: true

428850
type: KineticLaw
local parameters: 569096
local parameters: 569095
notes: k1*Ras_slash_inact_minus_GEF*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_act_minus_GEF_slash_PKC_minus_act_minus_GEF_cplx

569096
type: LocalParameter
units: 424878
value: 2.4E-14

569095
type: LocalParameter
units: 424962
value: 9.000045E-15

428838
type: SpeciesReference
stoichiometry: 1.0
species: 400678

428825
type: SpeciesReference
stoichiometry: 1.0
species: 404297

428813
type: SpeciesReference
stoichiometry: 1.0
species: 401917

405517
type: Reaction
kinetic law: 427457
product: 427445
reactant: 427433
reactant: 427420
notes: K inhib = 1nM from Cohen Ann Rev Bioch 1989, 4 nM from Foukes et al Assume 2 nM. kf /kb = 8.333e-4
fast: false
reversible: true

427457
type: KineticLaw
local parameters: 568986
local parameters: 568983
notes: kf*PP1_slash_I1_star_*PP1_minus_active-kb*PP1_slash_PP1_minus_I1_star_

568986
type: LocalParameter
units: 424878
value: 1.5E-16

568983
type: LocalParameter
units: 424962
value: 7.499655E-13

427445
type: SpeciesReference
stoichiometry: 1.0
species: 403137

427433
type: SpeciesReference
stoichiometry: 1.0
species: 402797

427420
type: SpeciesReference
stoichiometry: 1.0
species: 403117

405257
type: Reaction
kinetic law: 426862
product: 426850
reactant: 426838
notes: The only clue I have to these rates is from the time courses of the EGF activation, which is around 1 to 5 min. The dephosph would be expected to be of the same order, perhaps a bit longer. Lets use 0.002 which is about 8 min. Sep 17: The transient activation curve matches better with kf = 0.001
fast: false
reversible: true

426862
type: KineticLaw
local parameters: 568938
local parameters: 568935
notes: kf*Sos_slash_Sos_star_-kb*Sos_slash_Sos

568938
type: LocalParameter
units: 424878
value: 0.0

568935
type: LocalParameter
units: 424878
value: 1.5E-18

426850
type: SpeciesReference
stoichiometry: 1.0
species: 402497

426838
type: SpeciesReference
stoichiometry: 1.0
species: 402477

402477
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

406317
type: Reaction
kinetic law: 429346
product: 429334
reactant: 429322
reactant: 429310
notes: 10 X raise oct 22 12 X further raise oct 24 to allow for correct conc of enzyme
fast: false
reversible: true

429346
type: KineticLaw
local parameters: 569117
local parameters: 569116
notes: k1*PLA2_slash_APC*PLA2_slash_PIP2_minus_PLA2_star_-k2*PLA2_slash_PIP2_minus_PLA2_star__slash_kenz_slash_kenz_cplx

569117
type: LocalParameter
units: 424878
value: 6.624E-14

569116
type: LocalParameter
units: 424962
value: 4.140045E-15

429334
type: SpeciesReference
stoichiometry: 1.0
species: 400837

429322
type: SpeciesReference
stoichiometry: 1.0
species: 400817

429310
type: SpeciesReference
stoichiometry: 1.0
species: 404077

405737
type: Reaction
kinetic law: 427991
product: 427979
product: 427967
reactant: 427955
notes: This has to be fast, as the activation of PKA by cAMP is also fast. kf was 10
fast: false
reversible: true

427991
type: KineticLaw
local parameters: 569030
local parameters: 569027
notes: kf*PKA_slash_R2C2_minus_cAMP4-kb*PKA_minus_active*PKA_slash_R2C_minus_cAMP4

569030
type: LocalParameter
units: 424962
value: 2.7E-14

569027
type: LocalParameter
units: 424878
value: 9.0E-14

427979
type: SpeciesReference
stoichiometry: 1.0
species: 403477

427967
type: SpeciesReference
stoichiometry: 1.0
species: 402137

427955
type: SpeciesReference
stoichiometry: 1.0
species: 403457

405097
type: Reaction
kinetic law: 426523
product: 426510
reactant: 426498
notes: Assume a reasonably good rate for dephosphorylating it, 1/sec
fast: false
reversible: true

426523
type: KineticLaw
local parameters: 568906
local parameters: 568903
notes: kf*Ras_slash_GAP_star_-kb*Ras_slash_GAP

568906
type: LocalParameter
units: 424878
value: 0.0

568903
type: LocalParameter
units: 424878
value: 1.5E-16

426510
type: SpeciesReference
stoichiometry: 1.0
species: 402037

426498
type: SpeciesReference
stoichiometry: 1.0
species: 402017

402017
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408417
type: Reaction
kinetic law: 434484
product: 434472
reactant: 434460
reactant: 434448
notes: Max activity ~10umol/min/mg in presence of lots of CaM. Affinity is low, 40 uM. k3 = 10, k2 = 40, k1 = (50/40) / 6e5.
fast: false
reversible: true

434484
type: KineticLaw
local parameters: 569332
local parameters: 569331
notes: k1*cAMP*AC_slash_CaM_dot_PDE1-k2*AC_slash_CaM_dot_PDE1_slash_CaM_dot_PDE1_slash_CaM_dot_PDE1_cplx

569332
type: LocalParameter
units: 424878
value: 6.0E-14

569331
type: LocalParameter
units: 424962
value: 1.89E-15

434472
type: SpeciesReference
stoichiometry: 1.0
species: 403877

434460
type: SpeciesReference
stoichiometry: 1.0
species: 403857

434448
type: SpeciesReference
stoichiometry: 1.0
species: 403557

405837
type: Reaction
kinetic law: 428221
product: 428209
reactant: 428197
reactant: 428185
notes: Half-max at around 3nM = kb/kf from fig 5 in Feinstein et al PNAS USA 88 10173-10177 1991 kf = kb/1800 = 5.56e-4 kb Ofer\'s thesis data indicates it is more like 2 nM. kf = kb/1200 = 8.33e-4
fast: false
reversible: true

428221
type: KineticLaw
local parameters: 569050
local parameters: 569047
notes: kf*AC_slash_AC2*Gs_minus_alpha-kb*AC_slash_AC2_minus_Gs

569050
type: LocalParameter
units: 424878
value: 1.5E-15

569047
type: LocalParameter
units: 424962
value: 7.499925E-13

428209
type: SpeciesReference
stoichiometry: 1.0
species: 403637

428197
type: SpeciesReference
stoichiometry: 1.0
species: 403897

428185
type: SpeciesReference
stoichiometry: 1.0
species: 403657

407577
type: Reaction
kinetic law: 432428
product: 432416
product: 432404
reactant: 432392
fast: false
reversible: false

432428
type: KineticLaw
local parameters: 569236
notes: k3*EGFR_slash_L_dot_EGFR_slash_phosph_Shc_slash_phosph_Shc_cplx

569236
type: LocalParameter
units: 424878
value: 3.0E-16

432416
type: SpeciesReference
stoichiometry: 1.0
species: 402297

432404
type: SpeciesReference
stoichiometry: 1.0
species: 402377

432392
type: SpeciesReference
stoichiometry: 1.0
species: 402337

404977
type: Reaction
kinetic law: 426266
product: 426254
reactant: 426242
reactant: 426230
notes: Lets try out the same kinetics as the Rec-Glu-bind-Gq This is much too forward. We know that the steady-state amount of Rec-Gq should be 40% of the total amount of receptor. This is for a different receptor, still we can try to match the value. kf = 1e-6 and kb = 1 give 0.333:0.8 which is pretty close.
fast: false
reversible: true

426266
type: KineticLaw
local parameters: 568882
local parameters: 568879
notes: kf*Gq_slash_G_minus_GDP*Gq_slash_mGluR-kb*Gq_slash_Rec_minus_Gq

568882
type: LocalParameter
units: 424878
value: 1.5E-15

568879
type: LocalParameter
units: 424962
value: 9.000045E-16

426254
type: SpeciesReference
stoichiometry: 1.0
species: 401337

426242
type: SpeciesReference
stoichiometry: 1.0
species: 401297

426230
type: SpeciesReference
stoichiometry: 1.0
species: 401277

407917
type: Reaction
kinetic law: 433273
product: 433261
reactant: 433249
reactant: 433237
fast: false
reversible: true

433273
type: KineticLaw
local parameters: 569276
local parameters: 569273
notes: k1*CaMKII_slash_CaMKII_minus_thr286*PP1_minus_active-k2*PP1_minus_active_slash_Deph_thr286b_slash_Deph_thr286b_cplx

569276
type: LocalParameter
units: 424878
value: 2.1E-15

569273
type: LocalParameter
units: 424962
value: 5.147955E-16

433261
type: SpeciesReference
stoichiometry: 1.0
species: 402897

433249
type: SpeciesReference
stoichiometry: 1.0
species: 402797

433237
type: SpeciesReference
stoichiometry: 1.0
species: 402677

408257
type: Reaction
kinetic law: 434096
modifier: 434084
product: 434072
reactant: 434060
fast: false
reversible: false

434096
type: KineticLaw
local parameters: 569315
local parameters: 569312
notes: kcat*AC_slash_AC1_minus_Gs*AC_slash_ATP/(Km+AC_slash_ATP)

569315
type: LocalParameter
units: 424842
value: 20.0

569312
type: LocalParameter
units: 424878
value: 2.7E-14

434072
type: SpeciesReference
stoichiometry: 1.0
species: 403557

434060
type: SpeciesReference
stoichiometry: 1.0
species: 404237

407657
type: Reaction
kinetic law: 432645
product: 432633
product: 432621
reactant: 432609
fast: false
reversible: false

432645
type: KineticLaw
local parameters: 569250
notes: k3*CaMKII_slash_tot_CaM_CaMKII_slash_CaM_act_305_slash_CaM_act_305_cplx

569250
type: LocalParameter
units: 424878
value: 9.0E-15

432633
type: SpeciesReference
stoichiometry: 1.0
species: 404317

432621
type: SpeciesReference
stoichiometry: 1.0
species: 402657

432609
type: SpeciesReference
stoichiometry: 1.0
species: 402717

406977
type: Reaction
kinetic law: 430978
product: 430966
product: 430954
reactant: 430942
fast: false
reversible: false

430978
type: KineticLaw
local parameters: 569181
notes: k3*MKP_minus_1_slash_MKP1_minus_tyr_minus_deph_slash_MKP1_minus_tyr_minus_deph_cplx

569181
type: LocalParameter
units: 424878
value: 6.0E-15

430966
type: SpeciesReference
stoichiometry: 1.0
species: 401717

430954
type: SpeciesReference
stoichiometry: 1.0
species: 401457

430942
type: SpeciesReference
stoichiometry: 1.0
species: 401737

408357
type: Reaction
kinetic law: 434337
product: 434325
product: 434313
reactant: 434301
fast: false
reversible: false

434337
type: KineticLaw
local parameters: 569327
notes: k3*AC_slash_cAMP_minus_PDE_star__slash_PDE_star__slash_PDE_star__cplx

569327
type: LocalParameter
units: 424878
value: 3.0E-14

434325
type: SpeciesReference
stoichiometry: 1.0
species: 403777

434313
type: SpeciesReference
stoichiometry: 1.0
species: 403697

434301
type: SpeciesReference
stoichiometry: 1.0
species: 403797

407497
type: Reaction
kinetic law: 432236
product: 432224
product: 432212
reactant: 432200
fast: false
reversible: false

432236
type: KineticLaw
local parameters: 569230
notes: k3*Shc_star__dot_Sos_dot_Grb2_slash_Sos_dot_Ras_GEF_slash_Sos_dot_Ras_GEF_cplx

569230
type: LocalParameter
units: 424878
value: 3.0E-17

432224
type: SpeciesReference
stoichiometry: 1.0
species: 402237

432212
type: SpeciesReference
stoichiometry: 1.0
species: 401977

432200
type: SpeciesReference
stoichiometry: 1.0
species: 402257

408177
type: Reaction
kinetic law: 433902
product: 433890
product: 433878
reactant: 433866
fast: false
reversible: false

433902
type: KineticLaw
local parameters: 569298
notes: k3*CaNAB_minus_Ca4_slash_dephosph_inhib1_noCaM_slash_dephosph_inhib1_noCaM_cplx

569298
type: LocalParameter
units: 424878
value: 5.1E-17

433890
type: SpeciesReference
stoichiometry: 1.0
species: 403237

433878
type: SpeciesReference
stoichiometry: 1.0
species: 403097

433866
type: SpeciesReference
stoichiometry: 1.0
species: 403257

406297
type: Reaction
kinetic law: 429298
product: 429286
product: 429274
reactant: 429262
fast: false
reversible: false

429298
type: KineticLaw
local parameters: 569115
notes: k3*PLA2_slash_PLA2_minus_Ca_star__slash_kenz_slash_kenz_cplx

569115
type: LocalParameter
units: 424878
value: 8.1E-15

429286
type: SpeciesReference
stoichiometry: 1.0
species: 400777

429274
type: SpeciesReference
stoichiometry: 1.0
species: 400657

429262
type: SpeciesReference
stoichiometry: 1.0
species: 400797

400519
type: Compartment
constant: true
size: 1.0E-18
spatial dimensions: 3.0

403957
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 400538

406397
type: Reaction
kinetic law: 429540
product: 429528
reactant: 429516
reactant: 429504
notes: 10 X raise oct 22 12 X raise oct 24 + conversion to k2 =4 * k3
fast: false
reversible: true

429540
type: KineticLaw
local parameters: 569126
local parameters: 569123
notes: k1*PLA2_slash_APC*PLA2_slash_DAG_minus_Ca_minus_PLA2_star_-k2*PLA2_slash_DAG_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

569126
type: LocalParameter
units: 424878
value: 3.6E-13

569123
type: LocalParameter
units: 424962
value: 2.250045E-14

429528
type: SpeciesReference
stoichiometry: 1.0
species: 400917

429516
type: SpeciesReference
stoichiometry: 1.0
species: 400897

429504
type: SpeciesReference
stoichiometry: 1.0
species: 404077

405897
type: Reaction
kinetic law: 428355
product: 428342
reactant: 428330
notes: The rates for this are poorly constrained. In adipocytes (probably a different PDE) the dephosphorylation is complete within 15 min, but there are no intermediate time points so it could be much faster. Identity of phosphatase etc is still unknown.
fast: false
reversible: true

428355
type: KineticLaw
local parameters: 569062
local parameters: 569059
notes: kf*AC_slash_cAMP_minus_PDE_star_-kb*AC_slash_cAMP_minus_PDE

569062
type: LocalParameter
units: 424878
value: 0.0

569059
type: LocalParameter
units: 424878
value: 1.5E-16

428342
type: SpeciesReference
stoichiometry: 1.0
species: 403737

428330
type: SpeciesReference
stoichiometry: 1.0
species: 403777

405417
type: Reaction
kinetic law: 427226
product: 427214
reactant: 427202
reactant: 427189
notes: Lets use the fast rate consts here. Since the rates are so different, I am not sure whether the order is relevant. These correspond to the TR2C fragment. We use the Martin et al rates here, plus the Drabicowski binding consts. All are scaled by 3X to cell temp. kf = 2e-10 kb = 72 Stemmer & Klee: K1=.9, K2=1.1. Assume 1.0uM for both. kb/kf=3.6e11. If kb=72, kf = 2e-10 (Exactly the same !)....
fast: false
reversible: true

427226
type: KineticLaw
local parameters: 568966
local parameters: 568963
notes: kf*CaM_slash_CaM*Ca^2-kb*CaM_minus_TR2_minus_Ca2

568966
type: LocalParameter
units: 424878
value: 1.08E-13

568963
type: LocalParameter
units: 424914
value: 1.08000135E-13

427214
type: SpeciesReference
stoichiometry: 1.0
species: 403017

427202
type: SpeciesReference
stoichiometry: 2.0
species: 403917

427189
type: SpeciesReference
stoichiometry: 1.0
species: 402917

405497
type: Reaction
kinetic law: 427408
product: 427396
reactant: 427384
notes: This is put in to keep the basal levels of neurogranin* experimentally reasonable. From various papers, specially Ramakers et al JBC 270:23 1995 13892-13898, it looks like the basal level of phosph is between 20 and 40%. I est around 25 % The kf of 0.005 gives around this level at basal PKC activity levels of 0.1 uM active PKC.
fast: false
reversible: true

427408
type: KineticLaw
local parameters: 568982
local parameters: 568979
notes: kf*CaM_slash_neurogranin_star_-kb*CaM_slash_neurogranin

568982
type: LocalParameter
units: 424878
value: 0.0

568979
type: LocalParameter
units: 424878
value: 7.5E-18

427396
type: SpeciesReference
stoichiometry: 1.0
species: 402977

427384
type: SpeciesReference
stoichiometry: 1.0
species: 402957

405977
type: Reaction
kinetic law: 428536
product: 428524
reactant: 428512
reactant: 428500
fast: false
reversible: true

428536
type: KineticLaw
local parameters: 569078
local parameters: 569075
notes: kf*PKM_slash_Ca_detector*Ca^2-kb*PKM_slash_Ca_dot_detector_complex

569078
type: LocalParameter
units: 424878
value: 6.0E-16

569075
type: LocalParameter
units: 424914
value: 1.500039E-16

428524
type: SpeciesReference
stoichiometry: 1.0
species: 404017

428512
type: SpeciesReference
stoichiometry: 2.0
species: 403917

428500
type: SpeciesReference
stoichiometry: 1.0
species: 403957

407197
type: Reaction
kinetic law: 431511
product: 431499
reactant: 431486
reactant: 431474
notes: Kinetics based on the activation of Gq by the receptor complex in the Gq model (in turn based on the Mahama and Linderman model) k1 = 2e-5, k2 = 1e-10, k3 = 10 (I do not know why they even bother with k2). Lets put k1 at 2e-6 to get a reasonable equilibrium More specific values from, eg.g: Orita et al JBC 268(34) 25542-25546 from rasGRF and smgGDS: k1=3.3e-7; k2 = 0.08, k3 = 0.02
fast: false
reversible: true

431511
type: KineticLaw
local parameters: 569201
local parameters: 569200
notes: k1*Ras_slash_GDP_minus_Ras*Ras_slash_GEF_minus_Gprot_minus_bg-k2*Ras_slash_GEF_minus_Gprot_minus_bg_slash_GEF_minus_bg_act_minus_ras_slash_GEF_minus_bg_act_minus_ras_cplx

569201
type: LocalParameter
units: 424878
value: 1.2E-16

569200
type: LocalParameter
units: 424962
value: 2.97E-16

431499
type: SpeciesReference
stoichiometry: 1.0
species: 401897

431486
type: SpeciesReference
stoichiometry: 1.0
species: 401877

431474
type: SpeciesReference
stoichiometry: 1.0
species: 401997

405577
type: Reaction
kinetic law: 427602
product: 427589
reactant: 427577
reactant: 427565
notes: going on the experience with CaM, we put the fast (high affinity) sites first. We only know (Stemmer and Klee) that the affinity is < 70 nM. Assuming 10 nM at first, we get kf = 2.78e-8, kb = 1. Try 20 nM. kf = 7e-9, kb = 1
fast: false
reversible: true

427602
type: KineticLaw
local parameters: 568998
local parameters: 568995
notes: kf*PP2B_slash_CaNAB*Ca^2-kb*PP2B_slash_CaNAB_minus_Ca2

568998
type: LocalParameter
units: 424878
value: 1.5E-15

568995
type: LocalParameter
units: 424914
value: 1.501254E-11

427589
type: SpeciesReference
stoichiometry: 1.0
species: 403297

427577
type: SpeciesReference
stoichiometry: 2.0
species: 403917

427565
type: SpeciesReference
stoichiometry: 1.0
species: 403277

400598
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 8.46311111111111E-23
initial amount: NaN
in compartment: 400538

408317
type: Reaction
kinetic law: 434241
product: 434229
product: 434217
reactant: 434205
fast: false
reversible: false

434241
type: KineticLaw
local parameters: 569324
notes: k3*AC_slash_cAMP_minus_PDE_slash_PDE_slash_PDE_cplx

569324
type: LocalParameter
units: 424878
value: 1.5E-14

434229
type: SpeciesReference
stoichiometry: 1.0
species: 403737

434217
type: SpeciesReference
stoichiometry: 1.0
species: 403697

434205
type: SpeciesReference
stoichiometry: 1.0
species: 403757

404277
type: Species
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

407717
type: Reaction
kinetic law: 432791
product: 432779
reactant: 432766
reactant: 432754
notes: See Hanson and Schulman again, for afterburst rates of phosph.
fast: false
reversible: true

432791
type: KineticLaw
local parameters: 569255
local parameters: 569254
notes: k1*CaMKII_slash_CaMKII_minus_thr286*CaMKII_slash_tot_autonomous_CaMKII-k2*CaMKII_slash_tot_autonomous_CaMKII_slash_auton_305_slash_auton_305_cplx

569255
type: LocalParameter
units: 424878
value: 3.6E-14

569254
type: LocalParameter
units: 424962
value: 2.571345E-16

432779
type: SpeciesReference
stoichiometry: 1.0
species: 402757

432766
type: SpeciesReference
stoichiometry: 1.0
species: 404337

432754
type: SpeciesReference
stoichiometry: 1.0
species: 402677

404477
type: Reaction
kinetic law: 425121
product: 425108
reactant: 425096
reactant: 425083
notes: Need est of rate. Assume it is fast Obtained from param search kf raised 10 X : see Shinomura et al PNAS 88 5149-5153 1991. kf changed from 3.865e-7 to 2.0e-7 in line with closer analysis of Shinomura data. 26 June 1996: Corrected DAG data: reduce kf 15x from 2e-7 to 1.333e-8
fast: false
reversible: true

425121
type: KineticLaw
local parameters: 568788
local parameters: 568787
notes: kf*DAG*PKC_slash_PKC_minus_Ca-kb*PKC_slash_PKC_minus_Ca_minus_DAG

568788
type: LocalParameter
units: 424878
value: 1.29522E-14

568787
type: LocalParameter
units: 424962
value: 1.1999745E-17

425108
type: SpeciesReference
stoichiometry: 1.0
species: 400598

425096
type: SpeciesReference
stoichiometry: 1.0
species: 400558

425083
type: SpeciesReference
stoichiometry: 1.0
species: 400638

406337
type: Reaction
kinetic law: 429395
product: 429382
product: 429370
reactant: 429358
fast: false
reversible: false

429395
type: KineticLaw
local parameters: 569118
notes: k3*PLA2_slash_PIP2_minus_PLA2_star__slash_kenz_slash_kenz_cplx

569118
type: LocalParameter
units: 424878
value: 1.656E-14

429382
type: SpeciesReference
stoichiometry: 1.0
species: 400817

429370
type: SpeciesReference
stoichiometry: 1.0
species: 400657

429358
type: SpeciesReference
stoichiometry: 1.0
species: 400837

406877
type: Reaction
kinetic law: 430726
product: 430714
reactant: 430702
reactant: 430690
notes: Kinetics are the same as for the craf-1* activity, ie., k1=1.1e-6, k2=.42, k3 =0.105 These are based on Force et al PNAS USA 91 1270-1274 1994. These parms cannot reach the observed 4X stim of MAPK. So lets increase the affinity, ie, raise k1 10X to 1.1e-5 Lets take it back down to where it was. Back up to 5X: 5.5e-6
fast: false
reversible: true

430726
type: KineticLaw
local parameters: 569171
local parameters: 569170
notes: k1*MAPK_slash_MAPKK*MAPK_slash_Raf_star__minus_GTP_minus_Ras-k2*MAPK_slash_Raf_star__minus_GTP_minus_Ras_slash_Raf_star__minus_GTP_minus_Ras_dot_1_slash_Raf_star__minus_GTP_minus_Ras_dot_1_cplx

569171
type: LocalParameter
units: 424878
value: 1.8E-15

569170
type: LocalParameter
units: 424962
value: 1.41426E-14

430714
type: SpeciesReference
stoichiometry: 1.0
species: 401677

430702
type: SpeciesReference
stoichiometry: 1.0
species: 401657

430690
type: SpeciesReference
stoichiometry: 1.0
species: 401437

407817
type: Reaction
kinetic law: 433032
product: 433020
product: 433008
reactant: 432996
fast: false
reversible: false

433032
type: KineticLaw
local parameters: 569265
notes: k3*PP1_minus_active_slash_Deph_minus_thr286_slash_Deph_minus_thr286_cplx

569265
type: LocalParameter
units: 424878
value: 5.25E-16

433020
type: SpeciesReference
stoichiometry: 1.0
species: 402797

433008
type: SpeciesReference
stoichiometry: 1.0
species: 402617

432996
type: SpeciesReference
stoichiometry: 1.0
species: 402817

402817
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

408017
type: Reaction
kinetic law: 433515
product: 433503
product: 433491
reactant: 433479
fast: false
reversible: false

433515
type: KineticLaw
local parameters: 569283
notes: k3*CaM_po_Ca_pc_n_minus_CaNAB_slash_dephosph_inhib1_slash_dephosph_inhib1_cplx

569283
type: LocalParameter
units: 424878
value: 5.1E-16

433503
type: SpeciesReference
stoichiometry: 1.0
species: 404357

433491
type: SpeciesReference
stoichiometry: 1.0
species: 403097

433479
type: SpeciesReference
stoichiometry: 1.0
species: 403057

407897
type: Reaction
kinetic law: 433225
product: 433213
product: 433200
reactant: 433188
fast: false
reversible: false

433225
type: KineticLaw
local parameters: 569271
notes: k3*PP1_minus_active_slash_Deph_minus_thr286c_slash_Deph_minus_thr286c_cplx

569271
type: LocalParameter
units: 424878
value: 5.25E-16

433213
type: SpeciesReference
stoichiometry: 1.0
species: 402797

433200
type: SpeciesReference
stoichiometry: 1.0
species: 402697

433188
type: SpeciesReference
stoichiometry: 1.0
species: 402877

404617
type: Reaction
kinetic law: 425437
product: 425425
reactant: 425413
reactant: 425401
notes: 27 June 1996 Scaled kf down by 0.015 from 3.33e-7 to 5e-9 to fit with revised DAG estimates and use of mole-fraction to calculate eff on PLA2.
fast: false
reversible: true

425437
type: KineticLaw
local parameters: 568810
local parameters: 568807
notes: kf*DAG*PLA2_slash_PLA2_minus_Ca_star_-kb*PLA2_slash_DAG_minus_Ca_minus_PLA2_star_

568810
type: LocalParameter
units: 424878
value: 6.0E-15

568807
type: LocalParameter
units: 424962
value: 4.499955E-18

425425
type: SpeciesReference
stoichiometry: 1.0
species: 400897

425413
type: SpeciesReference
stoichiometry: 1.0
species: 400777

425401
type: SpeciesReference
stoichiometry: 1.0
species: 400638

406177
type: Reaction
kinetic law: 428996
product: 428984
product: 428972
reactant: 428959
fast: false
reversible: false

428996
type: KineticLaw
local parameters: 569103
notes: k3*PKC_minus_active_slash_PKC_minus_phosph_minus_neurogranin_slash_PKC_minus_phosph_minus_neurogranin_cplx

569103
type: LocalParameter
units: 424878
value: 8.7E-16

428984
type: SpeciesReference
stoichiometry: 1.0
species: 404297

428972
type: SpeciesReference
stoichiometry: 1.0
species: 402957

428959
type: SpeciesReference
stoichiometry: 1.0
species: 400697

406617
type: Reaction
kinetic law: 430085
product: 430073
product: 430061
product: 430049
reactant: 430037
fast: false
reversible: false

430085
type: KineticLaw
local parameters: 569145
notes: k3*PLCbeta_slash_PLC_minus_Ca_slash_PLC_minus_Ca_slash_PLC_minus_Ca_cplx

569145
type: LocalParameter
units: 424878
value: 1.5E-14

430073
type: SpeciesReference
stoichiometry: 1.0
species: 401117

430061
type: SpeciesReference
stoichiometry: 1.0
species: 401077

430049
type: SpeciesReference
stoichiometry: 1.0
species: 400638

430037
type: SpeciesReference
stoichiometry: 1.0
species: 401137

406697
type: Reaction
kinetic law: 430291
product: 430278
product: 430266
reactant: 430254
fast: false
reversible: false

430291
type: KineticLaw
local parameters: 569154
notes: k3*MAPK_slash_MAPKK_star__slash_MAPKKtyr_slash_MAPKKtyr_cplx

569154
type: LocalParameter
units: 424878
value: 4.5E-16

430278
type: SpeciesReference
stoichiometry: 1.0
species: 401517

430266
type: SpeciesReference
stoichiometry: 1.0
species: 401497

430254
type: SpeciesReference
stoichiometry: 1.0
species: 401537

407977
type: Reaction
kinetic law: 433419
product: 433407
product: 433395
reactant: 433383
fast: false
reversible: false

433419
type: KineticLaw
local parameters: 569280
notes: k3*CaM_po_Ca_pc_n_minus_CaNAB_slash_dephosph_neurogranin_slash_dephosph_neurogranin_cplx

569280
type: LocalParameter
units: 424878
value: 1.005E-15

433407
type: SpeciesReference
stoichiometry: 1.0
species: 404357

433395
type: SpeciesReference
stoichiometry: 1.0
species: 402977

433383
type: SpeciesReference
stoichiometry: 1.0
species: 403037

403437
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

405117
type: Reaction
kinetic law: 426572
product: 426560
reactant: 426548
reactant: 426536
notes: We have no numbers for this. It is probably between the two extremes represented by the CaMKII phosph states, and I have used guesses based on this. kf=1e-4 kb=1 The reaction is based on Farnsworth et al Nature 376 524-527 1995
fast: false
reversible: true

426572
type: KineticLaw
local parameters: 568910
local parameters: 568907
notes: kf*Ras_slash_inact_minus_GEF*CaM_minus_Ca4-kb*Ras_slash_CaM_minus_GEF

568910
type: LocalParameter
units: 424878
value: 1.5E-15

568907
type: LocalParameter
units: 424962
value: 2.99997E-13

426560
type: SpeciesReference
stoichiometry: 1.0
species: 402097

426548
type: SpeciesReference
stoichiometry: 1.0
species: 402217

426536
type: SpeciesReference
stoichiometry: 1.0
species: 401917

407797
type: Reaction
kinetic law: 432984
product: 432972
reactant: 432960
reactant: 432948
notes: The rates are from Stralfors et al Eur J Biochem 149 295-303 giving Vmax = 5.7 umol/min giving k3 = 3.5/sec and k2 = 14. Foulkes et al Eur J Biochem 132 309-313 1983 give Km = 5.1 uM so k1 becomes 5.72e-6 Simonelli 1984 (Grad Thesis, CUNY) showed that other substrates are about 1/10 rate of phosphorylase a, so we reduce k1,k2,k3 by 10 to 5.72e-7, 1.4, 0.35
fast: false
reversible: true

432984
type: KineticLaw
local parameters: 569264
local parameters: 569263
notes: k1*CaMKII_slash_CaMKII_minus_thr286_star__minus_CaM*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr286_slash_Deph_minus_thr286_cplx

569264
type: LocalParameter
units: 424878
value: 2.1E-15

569263
type: LocalParameter
units: 424962
value: 5.147955E-16

432972
type: SpeciesReference
stoichiometry: 1.0
species: 402817

432960
type: SpeciesReference
stoichiometry: 1.0
species: 402797

432948
type: SpeciesReference
stoichiometry: 1.0
species: 402637

407857
type: Reaction
kinetic law: 433128
product: 433116
product: 433104
reactant: 433092
fast: false
reversible: false

433128
type: KineticLaw
local parameters: 569268
notes: k3*PP1_minus_active_slash_Deph_minus_thr306_slash_Deph_minus_thr306_cplx

569268
type: LocalParameter
units: 424878
value: 5.25E-16

433116
type: SpeciesReference
stoichiometry: 1.0
species: 402797

433104
type: SpeciesReference
stoichiometry: 1.0
species: 402597

433092
type: SpeciesReference
stoichiometry: 1.0
species: 402857

406097
type: Reaction
kinetic law: 428801
product: 428789
product: 428776
reactant: 428764
fast: false
reversible: false

428801
type: KineticLaw
local parameters: 569094
notes: k3*PKC_minus_active_slash_PKC_minus_inact_minus_GAP_slash_PKC_minus_inact_minus_GAP_cplx

569094
type: LocalParameter
units: 424878
value: 6.0E-15

428789
type: SpeciesReference
stoichiometry: 1.0
species: 404297

428776
type: SpeciesReference
stoichiometry: 1.0
species: 402017

428764
type: SpeciesReference
stoichiometry: 1.0
species: 400677

407137
type: Reaction
kinetic law: 431366
product: 431354
product: 431342
reactant: 431330
fast: false
reversible: false

569196
type: LocalParameter
units: 424878
value: 9.0E-15

431354
type: SpeciesReference
stoichiometry: 1.0
species: 401777

431342
type: SpeciesReference
stoichiometry: 1.0
species: 401437

431330
type: SpeciesReference
stoichiometry: 1.0
species: 401837

404637
type: Reaction
kinetic law: 425473
product: 425461
reactant: 425449
notes: I need to check if the AA degradation pathway really leads back to APC. Anyway, it is a convenient buffered pool to dump it back into. For the purposes of the full model we use a rate of degradation of 0.2/sec Raised decay to 0.4 : see PLA35.g notes for Feb17
fast: false
reversible: true

425473
type: KineticLaw
local parameters: 568814
local parameters: 568811
notes: kf*AA-kb*PLA2_slash_APC

568814
type: LocalParameter
units: 424878
value: 0.0

568811
type: LocalParameter
units: 424878
value: 6.0E-16

425461
type: SpeciesReference
stoichiometry: 1.0
species: 404077

425449
type: SpeciesReference
stoichiometry: 1.0
species: 400657

406197
type: Reaction
kinetic law: 429044
product: 429032
reactant: 429020
reactant: 429008
notes: Rates are 60% those of PKC-phosph-neurogranin. See Huang et al ABB 305:2 570-580 1993
fast: false
reversible: true

429044
type: KineticLaw
local parameters: 569105
local parameters: 569104
notes: k1*CaM_slash_neurogranin_minus_CaM*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_phosph_minus_ng_minus_CaM_slash_PKC_minus_phosph_minus_ng_minus_CaM_cplx

569105
type: LocalParameter
units: 424878
value: 2.1E-15

569104
type: LocalParameter
units: 424962
value: 9.18E-17

429032
type: SpeciesReference
stoichiometry: 1.0
species: 400717

429020
type: SpeciesReference
stoichiometry: 1.0
species: 404297

429008
type: SpeciesReference
stoichiometry: 1.0
species: 402937

407317
type: Reaction
kinetic law: 431800
product: 431788
reactant: 431776
reactant: 431764
notes: Kinetics same as GEF-bg_act-ras
fast: false
reversible: true

431800
type: KineticLaw
local parameters: 569213
local parameters: 569212
notes: k1*Ras_slash_GDP_minus_Ras*Ras_slash_CaM_minus_GEF-k2*Ras_slash_CaM_minus_GEF_slash_CaM_minus_GEF_minus_act_minus_ras_slash_CaM_minus_GEF_minus_act_minus_ras_cplx

569213
type: LocalParameter
units: 424878
value: 1.2E-16

569212
type: LocalParameter
units: 424962
value: 2.97E-16

431788
type: SpeciesReference
stoichiometry: 1.0
species: 402117

431776
type: SpeciesReference
stoichiometry: 1.0
species: 402097

431764
type: SpeciesReference
stoichiometry: 1.0
species: 401997

405697
type: Reaction
kinetic law: 427894
product: 427882
reactant: 427870
reactant: 427857
fast: false
reversible: true

427894
type: KineticLaw
local parameters: 569022
local parameters: 569019
notes: kf*PKA_slash_R2C2_minus_cAMP2*cAMP-kb*PKA_slash_R2C2_minus_cAMP3

569022
type: LocalParameter
units: 424878
value: 1.65E-13

569019
type: LocalParameter
units: 424962
value: 1.1249955E-13

427882
type: SpeciesReference
stoichiometry: 1.0
species: 403437

427870
type: SpeciesReference
stoichiometry: 1.0
species: 403557

427857
type: SpeciesReference
stoichiometry: 1.0
species: 403417

404717
type: Reaction
kinetic law: 425642
product: 425630
reactant: 425618
notes: The enzyme is IP3 5-phosphomonesterase. about 45K. Actual products are Ins(1,4)P2, and cIns(1:2,4,5)P3. review in Majerus et al Science 234 1519-1526, 1986. Meyer and Stryer 1988 PNAS 85:5051-5055 est decay of IP3 at 1-3/sec
fast: false
reversible: true

425642
type: KineticLaw
local parameters: 568830
local parameters: 568827
notes: kf*IP3-kb*PLCbeta_slash_Inositol

568830
type: LocalParameter
units: 424878
value: 0.0

568827
type: LocalParameter
units: 424878
value: 3.75E-15

425630
type: SpeciesReference
stoichiometry: 1.0
species: 404137

404137
type: Species
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 400538

425618
type: SpeciesReference
stoichiometry: 1.0
species: 401077

406757
type: Reaction
kinetic law: 430436
product: 430424
reactant: 430412
reactant: 430400
fast: false
reversible: true

430436
type: KineticLaw
local parameters: 569159
local parameters: 569158
notes: k1*CaMKII_slash_CaMKII_star__star__star_*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr305_slash_Deph_minus_thr305_cplx

569159
type: LocalParameter
units: 424878
value: 2.1E-15

569158
type: LocalParameter
units: 424962
value: 5.147955E-16

430424
type: SpeciesReference
stoichiometry: 1.0
species: 402837

430412
type: SpeciesReference
stoichiometry: 1.0
species: 402797

430400
type: SpeciesReference
stoichiometry: 1.0
species: 402657

406477
type: Reaction
kinetic law: 429734
product: 429722
reactant: 429710
reactant: 429698
notes: Km = 25uM @ 50 uM ATP and 1mg/ml MBP (huge XS of substrate) Vmax = 4124 pmol/min/ml at a conc of 125 pmol/ml of enz, so: k3 = .5/sec (rate limiting) k1 = (k2 + k3)/Km = (.5 + 0)/(25*6e5) = 2e-8 (#/cell)^-1 #s from Sanghera et al JBC 265 pp 52 , 1990. From Nemenoff et al JBC 268(3):1960-1964 - using Sanghera\'s 1e-4 ratio of MAPK to protein, we get k3 = 7/sec from 1000 pmol/min/mg fig 5
fast: false
reversible: true

429734
type: KineticLaw
local parameters: 569132
local parameters: 569131
notes: k1*PLA2_slash_PLA2_minus_cytosolic*MAPK_star_-k2*MAPK_star__slash_MAPK_star__slash_MAPK_star__cplx

569132
type: LocalParameter
units: 424878
value: 6.0E-14

569131
type: LocalParameter
units: 424962
value: 2.925045E-15

429722
type: SpeciesReference
stoichiometry: 1.0
species: 401017

429710
type: SpeciesReference
stoichiometry: 1.0
species: 400997

429698
type: SpeciesReference
stoichiometry: 1.0
species: 400757

406717
type: Reaction
kinetic law: 430339
product: 430327
reactant: 430316
reactant: 430304
notes: Rate consts same as for MAPKKtyr.
fast: false
reversible: true

430339
type: KineticLaw
local parameters: 569156
local parameters: 569155
notes: k1*MAPK_slash_MAPK_minus_tyr*MAPK_slash_MAPKK_star_-k2*MAPK_slash_MAPKK_star__slash_MAPKKthr_slash_MAPKKthr_cplx

569156
type: LocalParameter
units: 424878
value: 1.8E-15

569155
type: LocalParameter
units: 424962
value: 4.86E-14

430327
type: SpeciesReference
stoichiometry: 1.0
species: 401557

430316
type: SpeciesReference
stoichiometry: 1.0
species: 401517

430304
type: SpeciesReference
stoichiometry: 1.0
species: 401497

404517
type: Reaction
kinetic law: 425194
product: 425182
reactant: 425170
notes: Raise kb from .087 to 0.1 to match data from Shinomura et al. Lower kf from 1.155 to 1.0 to match data from Shinomura et al.
fast: false
reversible: true

425194
type: KineticLaw
local parameters: 568792
local parameters: 568791
notes: kf*PKC_slash_PKC_minus_Ca_minus_DAG-kb*PKC_slash_PKC_minus_DAG_minus_memb_star_

568792
type: LocalParameter
units: 424878
value: 1.5E-16

568791
type: LocalParameter
units: 424878
value: 1.5E-15

425182
type: SpeciesReference
stoichiometry: 1.0
species: 400597

425170
type: SpeciesReference
stoichiometry: 1.0
species: 400598

406577
type: Reaction
kinetic law: 429977
product: 429965
product: 429953
reactant: 429940
fast: false
reversible: false

429977
type: KineticLaw
local parameters: 569142
notes: k3*MAPK_star__slash_phosph_Sos_slash_phosph_Sos_cplx

569142
type: LocalParameter
units: 424878
value: 1.5E-14

429965
type: SpeciesReference
stoichiometry: 1.0
species: 400997

429953
type: SpeciesReference
stoichiometry: 1.0
species: 402477

429940
type: SpeciesReference
stoichiometry: 1.0
species: 401057

406917
type: Reaction
kinetic law: 430828
product: 430815
reactant: 430802
reactant: 430789
notes: Same kinetics as other c-raf activated forms. See Force et al PNAS 91 1270-1274 1994. k1 = 1.1e-6, k2 = .42, k3 = 1.05 raise k1 to 5.5e-6
fast: false
reversible: true

430828
type: KineticLaw
local parameters: 569177
local parameters: 569174
notes: k1*MAPK_slash_MAPKK_minus_ser*MAPK_slash_Raf_star__minus_GTP_minus_Ras-k2*MAPK_slash_Raf_star__minus_GTP_minus_Ras_slash_Raf_star__minus_GTP_minus_Ras_dot_2_slash_Raf_star__minus_GTP_minus_Ras_dot_2_cplx

569177
type: LocalParameter
units: 424878
value: 1.8E-15

569174
type: LocalParameter
units: 424962
value: 1.41426E-14

430815
type: SpeciesReference
stoichiometry: 1.0
species: 401697

430802
type: SpeciesReference
stoichiometry: 1.0
species: 401657

430789
type: SpeciesReference
stoichiometry: 1.0
species: 401577

408497
type: Reaction
kinetic law: 434677
product: 434664
reactant: 434652
reactant: 434640
fast: false
reversible: true

434677
type: KineticLaw
local parameters: 569341
local parameters: 569340
notes: k1*PKM_slash_PKM_activator*PKM_slash_Ca_dot_detector_complex-k2*PKM_slash_Ca_dot_detector_complex_slash_kenz_slash_kenz_cplx

569341
type: LocalParameter
units: 424878
value: 1.2E-15

569340
type: LocalParameter
units: 424962
value: 2.99997E-16

434664
type: SpeciesReference
stoichiometry: 1.0
species: 404037

434652
type: SpeciesReference
stoichiometry: 1.0
species: 404017

434640
type: SpeciesReference
stoichiometry: 1.0
species: 404057

407237
type: Reaction
kinetic law: 431608
product: 431596
reactant: 431584
reactant: 431572
notes: Kinetics same as GEF-bg-act-ras
fast: false
reversible: true

431608
type: KineticLaw
local parameters: 569207
local parameters: 569204
notes: k1*Ras_slash_GDP_minus_Ras*Ras_slash_GEF_star_-k2*Ras_slash_GEF_star__slash_GEF_star__minus_act_minus_ras_slash_GEF_star__minus_act_minus_ras_cplx

569207
type: LocalParameter
units: 424878
value: 1.2E-16

569204
type: LocalParameter
units: 424962
value: 2.97E-16

431596
type: SpeciesReference
stoichiometry: 1.0
species: 401957

431584
type: SpeciesReference
stoichiometry: 1.0
species: 401937

431572
type: SpeciesReference
stoichiometry: 1.0
species: 401997

405177
type: Reaction
kinetic law: 426692
product: 426680
reactant: 426668
notes: Time course of decline of phosph is 20 min. Part of this is the turnoff time of the EGFR itself. Lets assume a tau of 10 min for this dephosph. It may be wildly off.
fast: false
reversible: true

426692
type: KineticLaw
local parameters: 568922
local parameters: 568919
notes: kf*EGFR_slash_SHC_star_-kb*EGFR_slash_SHC

568922
type: LocalParameter
units: 424878
value: 0.0

568919
type: LocalParameter
units: 424878
value: 2.50005E-18

426680
type: SpeciesReference
stoichiometry: 1.0
species: 402357

426668
type: SpeciesReference
stoichiometry: 1.0
species: 402377

405997
type: Reaction
kinetic law: 428572
product: 428560
reactant: 428548
notes: Time-course of 2 hours.
fast: false
reversible: true

428572
type: KineticLaw
local parameters: 569082
local parameters: 569079
notes: kf*PKC_slash_PKM_minus_zeta-kb*PKM_slash_degraded_PKM

569082
type: LocalParameter
units: 424878
value: 0.0

569079
type: LocalParameter
units: 424878
value: 7.5E-19

428560
type: SpeciesReference
stoichiometry: 1.0
species: 404277

428548
type: SpeciesReference
stoichiometry: 1.0
species: 400637

405637
type: Reaction
kinetic law: 427748
product: 427735
reactant: 427723
reactant: 427711
fast: false
reversible: true

427748
type: KineticLaw
local parameters: 569010
local parameters: 569007
notes: kf*CaM_minus_Ca4*CaNAB_minus_Ca4-kb*PP2B_slash_CaMCa4_minus_CaNAB

569010
type: LocalParameter
units: 424878
value: 1.5E-15

569007
type: LocalParameter
units: 424962
value: 9.000045E-13

427735
type: SpeciesReference
stoichiometry: 1.0
species: 403357

427723
type: SpeciesReference
stoichiometry: 1.0
species: 403237

427711
type: SpeciesReference
stoichiometry: 1.0
species: 402217

405217
type: Reaction
kinetic law: 426778
product: 426765
reactant: 426753
reactant: 426741
notes: Sasaoka et al JBC 269:51 pp 32621 1994, table on pg 32623 indicates that this pathway accounts for about 50% of the GEF activation. (88% - 39%). Error is large, about 20%. Fig 1 is most useful in constraining rates. Chook et al JBC 271:48 pp 30472, 1996 say that the Kd is 0.2 uM for Shc binding to EGFR. The Kd for Grb direct binding is 0.7, so we\'ll ignore it.
fast: false
reversible: true

426778
type: KineticLaw
local parameters: 568930
local parameters: 568927
notes: kf*Sos_slash_Sos_dot_Grb2*EGFR_slash_SHC_star_-kb*Shc_star__dot_Sos_dot_Grb2

568930
type: LocalParameter
units: 424878
value: 1.5E-16

568927
type: LocalParameter
units: 424962
value: 7.499655E-16

426765
type: SpeciesReference
stoichiometry: 1.0
species: 402237

426753
type: SpeciesReference
stoichiometry: 1.0
species: 402377

426741
type: SpeciesReference
stoichiometry: 1.0
species: 402457

406817
type: Reaction
kinetic law: 430582
product: 430570
product: 430558
reactant: 430546
fast: false
reversible: false

430582
type: KineticLaw
local parameters: 569166
notes: k3*MAPK_slash_Raf_minus_GTP_minus_Ras_slash_Raf_minus_GTP_minus_Ras_dot_1_slash_Raf_minus_GTP_minus_Ras_dot_1_cplx

569166
type: LocalParameter
units: 424878
value: 4.5E-16

430570
type: SpeciesReference
stoichiometry: 1.0
species: 401597

430558
type: SpeciesReference
stoichiometry: 1.0
species: 401577

430546
type: SpeciesReference
stoichiometry: 1.0
species: 401617

406537
type: Reaction
kinetic law: 429879
product: 429867
product: 429855
reactant: 429843
fast: false
reversible: false

429879
type: KineticLaw
local parameters: 569139
notes: k3*MAPK_star__slash_MAPK_star__minus_feedback_slash_MAPK_star__minus_feedback_cplx

569139
type: LocalParameter
units: 424878
value: 1.5E-14

429867
type: SpeciesReference
stoichiometry: 1.0
species: 400997

429855
type: SpeciesReference
stoichiometry: 1.0
species: 401477

429843
type: SpeciesReference
stoichiometry: 1.0
species: 401037

405237
type: Reaction
kinetic law: 426826
product: 426814
reactant: 426802
reactant: 426790
notes: Same rates as Grb2_bind_Sos: Porfiri and McCormick JBC 271:10 pp 5871 1996 show that the binding is not affected by the phosph.
fast: false
reversible: true

426826
type: KineticLaw
local parameters: 568934
local parameters: 568931
notes: kf*Sos_slash_Sos_star_*Sos_slash_Grb2-kb*Sos_slash_Sos_star__dot_Grb2

568934
type: LocalParameter
units: 424878
value: 2.52E-17

568931
type: LocalParameter
units: 424962
value: 3.75003E-17

426814
type: SpeciesReference
stoichiometry: 1.0
species: 402417

426802
type: SpeciesReference
stoichiometry: 1.0
species: 402437

426790
type: SpeciesReference
stoichiometry: 1.0
species: 402477

404697
type: Reaction
kinetic law: 425606
product: 425594
reactant: 425581
reactant: 425569
notes: Affinity for Ca = 1uM without AlF, 0.1 with: from Smrcka et al science 251 pp 804-807 1991 so [Ca].kf = kb so kb/kf = 1 * 6e5 = 1/1.66e-6 11 June 1996: Raised affinity to 5e-6 to maintain balance. See notes.
fast: false
reversible: true

425606
type: KineticLaw
local parameters: 568826
local parameters: 568823
notes: kf*Ca*PLCbeta_slash_PLC-kb*PLCbeta_slash_PLC_minus_Ca

568826
type: LocalParameter
units: 424878
value: 1.5E-15

568823
type: LocalParameter
units: 424962
value: 4.499955E-15

425594
type: SpeciesReference
stoichiometry: 1.0
species: 401117

425581
type: SpeciesReference
stoichiometry: 1.0
species: 401097

401097
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.8
initial amount: NaN
in compartment: 400538

425569
type: SpeciesReference
stoichiometry: 1.0
species: 403917

405717
type: Reaction
kinetic law: 427943
product: 427931
reactant: 427918
reactant: 427906
fast: false
reversible: true

427943
type: KineticLaw
local parameters: 569026
local parameters: 569023
notes: kf*cAMP*PKA_slash_R2C2_minus_cAMP3-kb*PKA_slash_R2C2_minus_cAMP4

569026
type: LocalParameter
units: 424878
value: 4.875E-14

569023
type: LocalParameter
units: 424962
value: 1.1249955E-13

427931
type: SpeciesReference
stoichiometry: 1.0
species: 403457

427918
type: SpeciesReference
stoichiometry: 1.0
species: 403437

427906
type: SpeciesReference
stoichiometry: 1.0
species: 403557

404797
type: Reaction
kinetic law: 425827
product: 425814
reactant: 425802
reactant: 425790
notes: this binding does not produce active PLC. This step was needed to implement the described (Smrcka et al) increase in affinity for Ca by PLC once Gq was bound. The kinetics are the same as the binding step for Ca-PLC to Gq. June 1996: Changed the kf to 4.2e-5 to 4.2e-6 to preserve balance around the reactions.
fast: false
reversible: true

425827
type: KineticLaw
local parameters: 568846
local parameters: 568843
notes: kf*PLCbeta_slash_PLC*G_star_GTP-kb*PLCbeta_slash_PLC_minus_Gq

568846
type: LocalParameter
units: 424878
value: 1.5E-15

568843
type: LocalParameter
units: 424962
value: 3.78E-15

425814
type: SpeciesReference
stoichiometry: 1.0
species: 401197

425802
type: SpeciesReference
stoichiometry: 1.0
species: 401237

425790
type: SpeciesReference
stoichiometry: 1.0
species: 401097

407617
type: Reaction
notes: Mainly Homma et al JBC 263:14 1988 pp 6592, but these parms are the Ca-stimulated form. It is not clear whether the enzyme is activated by tyrosine phosphorylation at this point or not. Wahl et al JBC 267:15 10447-10456 1992 say that this has 7X higher affinity for substrate than control.
reversible: false
fast: false
kinetic law: 432549
reactant: 432501
product: 432525
product: 432513
modifier: 432537

432549
type: KineticLaw
local parameters: 569245
local parameters: 569242
notes: kcat*PLC_g_slash_Ca_dot_PLC_g_star_*PIP2/(Km+PIP2)

569245
type: LocalParameter
units: 424842
value: 19.7916666666667

569242
type: LocalParameter
units: 424878
value: 8.55E-14

432501
type: SpeciesReference
stoichiometry: 1.0
species: 404177

432525
type: SpeciesReference
stoichiometry: 1.0
species: 401077

432513
type: SpeciesReference
stoichiometry: 1.0
species: 400638

407257
type: Reaction
kinetic law: 431656
product: 431644
product: 431632
reactant: 431620
fast: false
reversible: false

431656
type: KineticLaw
local parameters: 569208
notes: k3*Ras_slash_GEF_star__slash_GEF_star__minus_act_minus_ras_slash_GEF_star__minus_act_minus_ras_cplx

569208
type: LocalParameter
units: 424878
value: 3.0E-17

431644
type: SpeciesReference
stoichiometry: 1.0
species: 401937

431632
type: SpeciesReference
stoichiometry: 1.0
species: 401977

431620
type: SpeciesReference
stoichiometry: 1.0
species: 401957

404957
type: Reaction
reactant: 426170
kinetic law: 426218
product: 426182
product: 426206
notes: This is the kcat==k3 stage of the Rec-Glu ezymatic activation of Gq. From Berstein et al actiation is at .35 - 0.7/min From Fay et al Biochem 30 5066-5075 1991 kf = .01/sec From Nakamura et al J physiol Lond 474:1 35-41 1994 see time courses. Also (Berstein) 15-40% of gprot is in GTP-bound form on stim.
product: 426194
fast: false
reversible: true

426170
type: SpeciesReference
stoichiometry: 1.0
species: 401357

426218
type: KineticLaw
local parameters: 568878
local parameters: 568875
notes: kf*Gq_slash_Rec_minus_Glu_minus_Gq-kb*G_star_GTP*BetaGamma*Gq_slash_Rec_minus_Glu

568878
type: LocalParameter
units: 424914
value: 0.0

568875
type: LocalParameter
units: 424878
value: 1.5E-17

426182
type: SpeciesReference
stoichiometry: 1.0
species: 401237

426206
type: SpeciesReference
stoichiometry: 1.0
species: 401317

426194
type: SpeciesReference
stoichiometry: 1.0
species: 401217

405877
type: Reaction
kinetic law: 428318
product: 428306
reactant: 428294
reactant: 428282
notes: kb/kf = 1.2 nM so kf = kb/720 = 1.3888 * kb.
fast: false
reversible: true

428318
type: KineticLaw
local parameters: 569058
local parameters: 569055
notes: kf*Gs_minus_alpha*AC_slash_AC2_star_-kb*AC_slash_AC2_star__minus_Gs

569058
type: LocalParameter
units: 424878
value: 1.5E-15

569055
type: LocalParameter
units: 424962
value: 1.2499245E-12

428306
type: SpeciesReference
stoichiometry: 1.0
species: 403717

428294
type: SpeciesReference
stoichiometry: 1.0
species: 403617

428282
type: SpeciesReference
stoichiometry: 1.0
species: 403897