BIOMD0000000439
type: SBMLModel
reaction: 478169
creator:
  ORG:
    orgname: University of Warwick
  n:
    given: Wayne
    family: Croft
species: 477065
reaction: 478023
time units: time
species: 477053
creator:
  ORG:
    orgname: University of Warwick
  n:
    given: Manuel
    family: Esparza-Franco
species: 477041
species: 477125
reaction: 477443
reaction: 477516
reaction: 477745
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
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
modified:
  W3 CDTF: Thu Jun 06 12:58:12 BST 2013
reaction: 478472
reaction: 477877
reaction: 477371
species: 476956
reaction: 478302
species: 477175
reaction: 478230
is: MODEL1212040001
species: 477163
reaction: 477951
reaction: 477601
is part of: GO:0008277
species: 477017
created:
  W3 CDTF: Wed Dec 05 13:20:07 GMT 2012
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

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

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

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

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

477113
type: Species
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

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

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

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

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

478193
type: SpeciesReference
stoichiometry: 1.0
species: 477077

477077
type: Species
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

478181
type: SpeciesReference
stoichiometry: 1.0
species: 477113

477065
type: Species
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

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

478059
type: SpeciesReference
stoichiometry: 1.0
species: 477125

477125
type: Species
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

478035
type: SpeciesReference
stoichiometry: 1.0
species: 477113

478047
type: SpeciesReference
stoichiometry: 1.0
species: 477053

477053
type: Species
in compartment: 476944
has only substance units: false
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

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

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

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

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

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

477041
type: Species
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

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

477455
type: SpeciesReference
stoichiometry: 1.0
species: 477005

477005
type: Species
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

477479
type: SpeciesReference
stoichiometry: 1.0
species: 477017

477017
type: Species
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

477504
type: LocalParameter
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

476968
type: Species
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

477467
type: SpeciesReference
stoichiometry: 1.0
species: 476968

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

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

477528
type: SpeciesReference
stoichiometry: 1.0
species: 477017

477564
type: SpeciesReference
stoichiometry: 1.0
species: 477041

477540
type: SpeciesReference
stoichiometry: 1.0
species: 476980

476980
type: Species
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

477552
type: SpeciesReference
stoichiometry: 1.0
species: 477029

477029
type: Species
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

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

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

477781
type: SpeciesReference
stoichiometry: 1.0
species: 477053

477769
type: SpeciesReference
stoichiometry: 1.0
species: 477077

477757
type: SpeciesReference
stoichiometry: 1.0
species: 477065

477150
type: Species
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

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

477188
type: Species
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

478581
type: SpeciesReference
stoichiometry: 1.0
species: 477188

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

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

477175
type: Species
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

478545
type: SpeciesReference
stoichiometry: 1.0
species: 477188

478532
type: SpeciesReference
stoichiometry: 1.0
species: 477175

477212
type: Parameter
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

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

477285
type: LocalParameter
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

477236
type: SpeciesReference
stoichiometry: 1.0
species: 476956

476956
type: Species
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

477249
type: SpeciesReference
stoichiometry: 1.0
species: 476968

477261
type: SpeciesReference
stoichiometry: 1.0
species: 476980

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

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

477841
type: SpeciesReference
stoichiometry: 1.0
species: 477077

477829
type: SpeciesReference
stoichiometry: 1.0
species: 477029

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

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

478387
type: SpeciesReference
stoichiometry: 1.0
species: 477150

477101
type: Species
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

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

478435
type: SpeciesReference
stoichiometry: 1.0
species: 477163

477163
type: Species
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

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

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

478132
type: SpeciesReference
stoichiometry: 1.0
species: 477053

478120
type: SpeciesReference
stoichiometry: 1.0
species: 477077

478108
type: SpeciesReference
stoichiometry: 1.0
species: 477125

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

477685
type: SpeciesReference
stoichiometry: 1.0
species: 477029

477709
type: SpeciesReference
stoichiometry: 1.0
species: 477065

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

477697
type: SpeciesReference
stoichiometry: 1.0
species: 477053

476993
type: Species
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

478606
type: Event
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

478618
type: Trigger
persistant: true
initial value: true

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

478496
type: SpeciesReference
stoichiometry: 1.0
species: 477175

478484
type: SpeciesReference
stoichiometry: 1.0
species: 477163

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

477890
type: SpeciesReference
stoichiometry: 1.0
species: 477089

477089
type: Species
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

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

477902
type: SpeciesReference
stoichiometry: 1.0
species: 477029

477914
type: SpeciesReference
stoichiometry: 1.0
species: 477101

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

477407
type: SpeciesReference
stoichiometry: 1.0
species: 477017

477383
type: SpeciesReference
stoichiometry: 1.0
species: 476980

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

477395
type: SpeciesReference
stoichiometry: 1.0
species: 476993

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

478315
type: SpeciesReference
stoichiometry: 1.0
species: 477138

477138
type: Species
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

478339
type: SpeciesReference
stoichiometry: 1.0
species: 476993

478327
type: SpeciesReference
stoichiometry: 1.0
species: 477041

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

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

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

478266
type: SpeciesReference
stoichiometry: 1.0
species: 477150

478254
type: SpeciesReference
stoichiometry: 1.0
species: 477138

478242
type: SpeciesReference
stoichiometry: 1.0
species: 477077

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

478011
type: LocalParameter
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

477987
type: SpeciesReference
stoichiometry: 1.0
species: 477089

477975
type: SpeciesReference
stoichiometry: 1.0
species: 477113

477963
type: SpeciesReference
stoichiometry: 1.0
species: 477101

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

477661
type: LocalParameter
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

477637
type: SpeciesReference
stoichiometry: 1.0
species: 477041

477625
type: SpeciesReference
stoichiometry: 1.0
species: 477029

477613
type: SpeciesReference
stoichiometry: 1.0
species: 476993

476846
type: SBMLUnitsDef
unit: 476859
name: hr

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

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

477323
type: SpeciesReference
stoichiometry: 1.0
species: 476993

477335
type: SpeciesReference
stoichiometry: 1.0
species: 477005

477359
type: LocalParameter
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

477310
type: SpeciesReference
stoichiometry: 1.0
species: 476956