476871
unit: 476883
name: 1/hr
type: SBMLUnitsDef

477709
stoichiometry: 1.0
species: 477065
type: SpeciesReference

478254
stoichiometry: 1.0
species: 477138
type: SpeciesReference

478520
kinetic law: 478557
modifier: 114482
product: 478545
reactant: 478532
fast: false
reversible: false
name: Delay 3
type: Reaction

478047
stoichiometry: 1.0
species: 477053
type: SpeciesReference

477914
stoichiometry: 1.0
species: 477101
type: SpeciesReference

476993
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: Gabg
type: Species

477637
stoichiometry: 1.0
species: 477041
type: SpeciesReference

477089
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 205.0
initial amount: NaN
in compartment: 476944
name: Effector
type: Species

477987
stoichiometry: 1.0
species: 477089
type: SpeciesReference

477479
stoichiometry: 1.0
species: 477017
type: SpeciesReference

476908
exponent: -1.0
scale: -9
multipler: 1.0
kind: MOLE
type: SBMLUnit

478387
stoichiometry: 1.0
species: 477150
type: SpeciesReference

478315
stoichiometry: 1.0
species: 477138
type: SpeciesReference

477310
stoichiometry: 1.0
species: 476956
type: SpeciesReference

477601
kinetic law: 477649
modifier: 114265
product: 477637
product: 477625
reactant: 477613
fast: false
reversible: false
name: Galpha activation spontaneous
type: Reaction

478193
stoichiometry: 1.0
species: 477077
type: SpeciesReference

477101
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: GaGTPEffector
type: Species

478120
stoichiometry: 1.0
species: 477077
type: SpeciesReference

477661
notes: The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.
units: 476871
value: 0.2
name: k6
type: LocalParameter

478169
kinetic law: 478205
modifier: 114397
product: 478193
reactant: 478181
fast: false
reversible: false
name: inertGalpha deactivation spontaneous
type: Reaction

477041
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 205.0
initial amount: NaN
in compartment: 476944
name: Gbg
type: Species

476932
exponent: -1.0
scale: 0
multipler: 3600.0
kind: SECOND
type: SBMLUnit

477504
notes: The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.
units: 476895
value: 0.005
name: k4
type: LocalParameter

476834
exponent: -1.0
scale: 0
multipler: 1.0
kind: LITRE
type: SBMLUnit

477200
constant: true
units: 476871
value: 1.5
name: ka
type: Parameter

478035
stoichiometry: 1.0
species: 477113
type: SpeciesReference

478618
persistant: true
initial value: true
type: Trigger

BIOMD0000000439
reaction: 478169
species: 477065
reaction: 478023
time units: time
species: 477053
created:
  W3 CDTF: Wed Dec 05 13:20:07 GMT 2012
species: 477041
species: 477125
reaction: 477443
reaction: 477516
reaction: 477745
type: SBMLModel
species: 477150
reaction: 478569
species: 476980
parameter: 477200
reaction: 478520
parameter: 477212
curated: true
reaction: 477224
name: Smith2009 - RGS mediated GTP hydrolysis
species: 477029
reaction: 477817
species: 477188
length unit: length
units def: 476871
species: 477113
reaction: 478375
species: 477101
units def: 476895
compartment: 476944
modified:
  W3 CDTF: Thu Jun 06 12:58:12 BST 2013
reaction: 478423
volume units: volume
reaction: 478096
reaction: 477673
notes: Smith2009 - RGS mediated GTP hydrolysis This model is described in the article: Dual positive and negative regulation of GPCR signaling by GTP hydrolysis. Smith B, Hill C, Godfrey EL, Rand D, van den Berg H, Thornton S, Hodgkin M, Davey J, Ladds G. Cell Signal. 2009 Jul;21(7):1151-60. Abstract: G protein-coupled receptors (GPCRs) regulate a variety of intracellular pathways through their ability to promote the binding of GTP to heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins increases the intrinsic GTPase activity of Galpha-subunits and are widely regarded as negative regulators of G protein signaling. Using yeast we demonstrate that GTP hydrolysis is not only required for desensitization, but is essential for achieving a high maximal (saturated level) response. Thus RGS-mediated GTP hydrolysis acts as both a negative (low stimulation) and positive (high stimulation) regulator of signaling. To account for this we generated a new kinetic model of the G protein cycle where Galpha(GTP) enters an inactive GTP-bound state following effector activation. Furthermore, in vivo and in silico experimentation demonstrates that maximum signaling output first increases and then decreases with RGS concentration. This unimodal, non-monotone dependence on RGS concentration is novel. Analysis of the kinetic model has revealed a dynamic network motif that shows precisely how inclusion of the inactive GTP-bound state for the Galpha produces this unimodal relationship. To reproduce dose-response plots in the publication, the model is simulated with 12 different concentrations (see parameter Ligand_conc). For each concentration, a single value must be obtained from the integral of the trajectory of species z3 from time=0 to time=30. These values are then used to build a dose-response plot (authors used GraphPad Prism). Mutant strains are simulated with alternative parameter values or initial conditions in Table S3. This model is hosted on BioModels Database and…
species: 476993
occurs in: http://identifiers.org/taxonomy/4932
event: 478606
area units: area
reaction: 478472
reaction: 477877
reaction: 477371
species: 476956
reaction: 478302
creator:
  ORG:
    orgname: University of Warwick
  n:
    given: Wayne
    family: Croft
species: 477175
reaction: 478230
is: MODEL1212040001
species: 477163
reaction: 477951
reaction: 477601
is part of: GO:0008277
creator:
  ORG:
    orgname: University of Warwick
  n:
    given: Manuel
    family: Esparza-Franco
species: 477017
substance units: substance
species: 476968
units def: 476846
species: 477138
species: 477005
species: 477089
reaction: 477297
units def: 476810
species: 477077
is described by: http://identifiers.org/pubmed/19285552

477443
reactant: 477455
type: Reaction
product: 477479
kinetic law: 477491
modifier: 114241
name: RGabg-Ligand association
reversible: false
reactant: 477467
fast: false
modifier: 114229

478545
stoichiometry: 1.0
species: 477188
type: SpeciesReference

477029
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: GaGTP
type: Species

478108
stoichiometry: 1.0
species: 477125
type: SpeciesReference

478059
stoichiometry: 1.0
species: 477125
type: SpeciesReference

478156
units: 476871
value: 0.3
name: k13
type: LocalParameter

477395
stoichiometry: 1.0
species: 476993
type: SpeciesReference

478242
stoichiometry: 1.0
species: 477077
type: SpeciesReference

478532
stoichiometry: 1.0
species: 477175
type: SpeciesReference

477733
units: 476895
value: 500.0
name: k7
type: LocalParameter

477902
stoichiometry: 1.0
species: 477029
type: SpeciesReference

477323
stoichiometry: 1.0
species: 476993
type: SpeciesReference

476968
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: L
type: Species

478375
kinetic law: 478399
modifier: 114445
reactant: 478387
fast: false
reversible: false
name: Phosphate degradation
type: Reaction

476883
exponent: -1.0
scale: 0
multipler: 3600.0
kind: SECOND
type: SBMLUnit

477188
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: z3
type: Species

477467
stoichiometry: 1.0
species: 476968
type: SpeciesReference

477540
stoichiometry: 1.0
species: 476980
type: SpeciesReference

477588
units: 476871
value: 50.0
name: k5
type: LocalParameter

477769
stoichiometry: 1.0
species: 477077
type: SpeciesReference

477053
in compartment: 476944
has only substance units: false
type: Species
initial concentration: 60.0
substance units: 476810
name: RGS
initial amount: NaN
boundary condition: false
constant: false
notes: NoRGS=0, 1xRGS=60, 2xRGS=120, 3xRGS=180

477673
name: Galpha-RGS association
modifier: 114277
reactant: 477685
modifier: 114289
product: 477709
type: Reaction
reversible: false
kinetic law: 477721
reactant: 477697
fast: false

478327
stoichiometry: 1.0
species: 477041
type: SpeciesReference

477455
stoichiometry: 1.0
species: 477005
type: SpeciesReference

477249
stoichiometry: 1.0
species: 476968
type: SpeciesReference

477865
units: 476871
value: 0.005
name: k9
type: LocalParameter

477175
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: z2
type: Species

478472
kinetic law: 478508
modifier: 114470
product: 478496
reactant: 478484
fast: false
reversible: false
name: Delay 2
type: Reaction

477890
stoichiometry: 1.0
species: 477089
type: SpeciesReference

477335
stoichiometry: 1.0
species: 477005
type: SpeciesReference

477516
kinetic law: 477576
reactant: 477528
product: 477564
modifier: 114253
reversible: false
fast: false
type: Reaction
product: 477540
name: Galpha activation by receptor
product: 477552

476920
exponent: 1.0
scale: 0
multipler: 1.0
kind: LITRE
type: SBMLUnit

477951
kinetic law: 477999
modifier: 114349
product: 477987
product: 477975
reactant: 477963
fast: false
reversible: false
name: Galpha becomes inert
type: Reaction

477212
notes: Dose-response plots use: 0.1, 1, 3.16228, 10, 31.6228, 100, 316.228, 1000, 3162.28, 10000, 31622.8, 100000
constant: true
units: 476810
value: 0.1
name: Ligand_conc
type: Parameter

476846
unit: 476859
name: hr
type: SBMLUnitsDef

477261
stoichiometry: 1.0
species: 476980
type: SpeciesReference

478411
units: 476871
value: 10.0
name: k17
type: LocalParameter

478023
type: Reaction
product: 478059
reactant: 478035
modifier: 114361
fast: false
reversible: false
name: inertGalpha-RGS association
reactant: 478047
modifier: 114373
kinetic law: 478072

476980
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: RL
type: Species

478290
units: 476871
value: 1000.0
name: k15
type: LocalParameter

477017
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: RGabgL
type: Species

477125
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: RGSinertGaGTP
type: Species

476810
unit: 476834
unit: 476822
name: nM
type: SBMLUnitsDef

478496
stoichiometry: 1.0
species: 477175
type: SpeciesReference

478363
units: 476895
value: 1000.0
name: k16
type: LocalParameter

476895
unit: 476932
unit: 476920
unit: 476908
name: 1/(nM*hr)
type: SBMLUnitsDef

477285
notes: The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.
units: 476895
value: 0.0025
name: k1
type: LocalParameter

478230
kinetic law: 478278
modifier: 114409
product: 478266
product: 478254
reactant: 478242
fast: false
reversible: false
name: Phosphate release
type: Reaction

477805
units: 476871
value: 2.5
name: k8
type: LocalParameter

477745
kinetic law: 477793
modifier: 114301
product: 477781
product: 477769
reactant: 477757
fast: false
reversible: false
name: Galpha deactivation by RGS
type: Reaction

477781
stoichiometry: 1.0
species: 477053
type: SpeciesReference

477065
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: RGSGaGTP
type: Species

477383
stoichiometry: 1.0
species: 476980
type: SpeciesReference

478581
stoichiometry: 1.0
species: 477188
type: SpeciesReference

477685
stoichiometry: 1.0
species: 477029
type: SpeciesReference

478011
notes: The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.
units: 476871
value: 1.0
name: k11
type: LocalParameter

477528
stoichiometry: 1.0
species: 477017
type: SpeciesReference

477963
stoichiometry: 1.0
species: 477101
type: SpeciesReference

476956
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 205.0
initial amount: NaN
in compartment: 476944
name: R
type: Species

477552
stoichiometry: 1.0
species: 477029
type: SpeciesReference

477163
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: z1
type: Species

478084
units: 476895
value: 50.0
name: k12
type: LocalParameter

478569
kinetic law: 478594
modifier: 114494
reactant: 478581
fast: false
reversible: false
name: Delay 4
type: Reaction

477877
reversible: false
reactant: 477890
name: Galpha-Effector association
modifier: 114337
type: Reaction
kinetic law: 477927
fast: false
reactant: 477902
product: 477914
modifier: 114325

477817
kinetic law: 477853
modifier: 114313
product: 477841
reactant: 477829
fast: false
reversible: false
name: Galpha deactivation spontaneous
type: Reaction

477138
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 205.0
initial amount: NaN
in compartment: 476944
name: GaGDP
type: Species

477625
stoichiometry: 1.0
species: 477029
type: SpeciesReference

478339
stoichiometry: 1.0
species: 476993
type: SpeciesReference

478423
kinetic law: 478459
modifier: 114457
modifier: 478447
product: 478435
fast: false
reversible: false
name: Delay 1
type: Reaction

477224
kinetic law: 477273
reactant: 477236
reactant: 477249
reversible: false
product: 477261
modifier: 114157
type: Reaction
fast: false
modifier: 114169
name: Receptor-Ligand association

477939
units: 476895
value: 10.0
name: k10
type: LocalParameter

477297
reactant: 477323
fast: false
product: 477335
reversible: false
kinetic law: 477347
modifier: 114181
reactant: 477310
modifier: 114193
name: Receptor-Gprotein association
type: Reaction

477150
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: P
type: Species

478606
event assignment: 478630
trigger: 478618
notes: The model in the publication uses a tanh step function to add ligand, but only because the solver used by the authors did not support Events. Results are identical using this event, and has been changed in agreement with the authors.
use values from trigger time: true
name: Ligand_addition
type: Event

478217
units: 476871
value: 0.005
name: k14
type: LocalParameter

477841
stoichiometry: 1.0
species: 477077
type: SpeciesReference

478484
stoichiometry: 1.0
species: 477163
type: SpeciesReference

477697
stoichiometry: 1.0
species: 477053
type: SpeciesReference

476859
exponent: 1.0
scale: 0
multipler: 3600.0
kind: SECOND
type: SBMLUnit

476822
exponent: 1.0
scale: -9
multipler: 1.0
kind: MOLE
type: SBMLUnit

477005
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: RGabg
type: Species

477113
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: inertGaGTP
type: Species

477077
constant: false
boundary condition: false
has only substance units: false
substance units: 476810
initial concentration: 0.0
initial amount: NaN
in compartment: 476944
name: GaGDPP
type: Species

478132
stoichiometry: 1.0
species: 477053
type: SpeciesReference

477371
fast: false
name: RL-Gprotein association
reversible: false
product: 477407
reactant: 477383
kinetic law: 477419
reactant: 477395
modifier: 114205
modifier: 114217
type: Reaction

477757
stoichiometry: 1.0
species: 477065
type: SpeciesReference

477407
stoichiometry: 1.0
species: 477017
type: SpeciesReference

477359
notes: The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.
units: 476895
value: 0.005
name: k2
type: LocalParameter

477431
units: 476895
value: 0.02
name: k3
type: LocalParameter

477829
stoichiometry: 1.0
species: 477029
type: SpeciesReference

476944
constant: true
size: 1.0
spatial dimensions: 3.0
name: cell
type: Compartment

478096
kinetic law: 478144
modifier: 114385
product: 478132
product: 478120
reactant: 478108
fast: false
reversible: false
name: inertGalpha deactivation by RGS
type: Reaction

477975
stoichiometry: 1.0
species: 477113
type: SpeciesReference

477564
stoichiometry: 1.0
species: 477041
type: SpeciesReference

478435
stoichiometry: 1.0
species: 477163
type: SpeciesReference

477236
stoichiometry: 1.0
species: 476956
type: SpeciesReference

478302
type: Reaction
name: Gprotein subunits association
reactant: 478315
reversible: false
fast: false
modifier: 114421
product: 478339
modifier: 114433
reactant: 478327
kinetic law: 478351

477613
stoichiometry: 1.0
species: 476993
type: SpeciesReference

478181
stoichiometry: 1.0
species: 477113
type: SpeciesReference

478266
stoichiometry: 1.0
species: 477150
type: SpeciesReference