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BIOMD0000000439 - Smith2009 - RGS mediated GTP hydrolysis

 

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Reference Publication
Publication ID: 19285552
Smith B, Hill C, Godfrey EL, Rand D, van den Berg H, Thornton S, Hodgkin M, Davey J, Ladds G.
Dual positive and negative regulation of GPCR signaling by GTP hydrolysis.
Cell. Signal. 2009 Jul; 21(7): 1151-1160
Molecular Organization and Assembly of Cells Centre, University of Warwick, Coventry, UK.  [more]
Model
Original Model: BIOMD0000000439.xml.origin
Submitter: Manuel Esparza-Franco
Submission ID: MODEL1212040001
Submission Date: 04 Dec 2012 15:09:35 UTC
Last Modification Date: 13 Mar 2014 18:13:04 UTC
Creation Date: 05 Dec 2012 13:20:07 UTC
Encoders:  Nick Juty
   Vijayalakshmi Chelliah
   Manuel Esparza-Franco
   Wayne Croft
set #1
bqmodel:isDerivedFrom PubMed 12446706
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #3
bqbiol:isPartOf Gene Ontology regulation of G-protein coupled receptor protein signaling pathway
set #4
bqbiol:hasTaxon Taxonomy Schizosaccharomyces pombe
Notes
Smith2009 - RGS mediated GTP hydrolysis

This model is described in the article:

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 identified by: MODEL1212040001 .

To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. PMID: 20587024 .

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 19285552 Submission Date: 04 Dec 2012 15:09:35 UTC Last Modification Date: 13 Mar 2014 18:13:04 UTC Creation Date: 05 Dec 2012 13:20:07 UTC
Mathematical expressions
Reactions
Receptor-Ligand association Receptor-Gprotein association RL-Gprotein association RGabg-Ligand association
Galpha activation by receptor Galpha activation spontaneous Galpha-RGS association Galpha deactivation by RGS
Galpha deactivation spontaneous Galpha-Effector association Galpha becomes inert inertGalpha-RGS association
inertGalpha deactivation by RGS inertGalpha deactivation spontaneous Phosphate release Gprotein subunits association
Phosphate degradation Delay 1 Delay 2 Delay 3
Delay 4      
Events
Ligand_addition      
Physical entities
Compartments Species
cell R L RL
Gabg RGabg RGabgL
GaGTP Gbg RGS
RGSGaGTP GaGDPP Effector
GaGTPEffector inertGaGTP RGSinertGaGTP
GaGDP P z1
z2 z3  
Global parameters
ka Ligand_conc    
Reactions (21)
 
 Receptor-Ligand association [R] + [L] → [RL];   {R} , {L}
 
 Receptor-Gprotein association [R] + [Gabg] → [RGabg];   {R} , {Gabg}
 
 RL-Gprotein association [RL] + [Gabg] → [RGabgL];   {RL} , {Gabg}
 
 RGabg-Ligand association [RGabg] + [L] → [RGabgL];   {RGabg} , {L}
 
 Galpha activation by receptor [RGabgL] → [RL] + [GaGTP] + [Gbg];   {RGabgL}
 
 Galpha activation spontaneous [Gabg] → [GaGTP] + [Gbg];   {Gabg}
 
 Galpha-RGS association [GaGTP] + [RGS] → [RGSGaGTP];   {GaGTP} , {RGS}
 
 Galpha deactivation by RGS [RGSGaGTP] → [GaGDPP] + [RGS];   {RGSGaGTP}
 
 Galpha deactivation spontaneous [GaGTP] → [GaGDPP];   {GaGTP}
 
 Galpha-Effector association [Effector] + [GaGTP] → [GaGTPEffector];   {Effector} , {GaGTP}
 
 Galpha becomes inert [GaGTPEffector] → [inertGaGTP] + [Effector];   {GaGTPEffector}
 
 inertGalpha-RGS association [inertGaGTP] + [RGS] → [RGSinertGaGTP];   {inertGaGTP} , {RGS}
 
 inertGalpha deactivation by RGS [RGSinertGaGTP] → [GaGDPP] + [RGS];   {RGSinertGaGTP}
 
 inertGalpha deactivation spontaneous [inertGaGTP] → [GaGDPP];   {inertGaGTP}
 
 Phosphate release [GaGDPP] → [GaGDP] + [P];   {GaGDPP}
 
 Gprotein subunits association [GaGDP] + [Gbg] → [Gabg];   {GaGDP} , {Gbg}
 
 Phosphate degradation [P] → ;   {P}
 
 Delay 1  → [z1];   {GaGTPEffector} , {GaGTPEffector}
 
 Delay 2 [z1] → [z2];   {z1}
 
 Delay 3 [z2] → [z3];   {z2}
 
 Delay 4 [z3] → ;   {z3}
 
Events (1)
 
 Ligand_addition
L = L+Ligand_conc
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 R
Compartment: cell
Initial concentration: 205.0  (Units: nanoMolar)
 
 L
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RL
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 Gabg
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RGabg
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RGabgL
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 GaGTP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 Gbg
Compartment: cell
Initial concentration: 205.0  (Units: nanoMolar)
 
 RGS
Compartment: cell
Initial concentration: 60.0  (Units: nanoMolar)
 
 RGSGaGTP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 GaGDPP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 Effector
Compartment: cell
Initial concentration: 205.0  (Units: nanoMolar)
 
 GaGTPEffector
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 inertGaGTP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RGSinertGaGTP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 GaGDP
Compartment: cell
Initial concentration: 205.0  (Units: nanoMolar)
 
 P
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 z1
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 z2
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 z3
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
Global Parameters (2)
 
   ka
Value: 1.5   (Units: 1/hr)
Constant
 
 Ligand_conc
Value: 0.1   (Units: nM)
Constant
 
Receptor-Ligand association (1)
 
 k1
Value: 0.0025   (Units: 1/(nM*hr))
Constant
 
Receptor-Gprotein association (1)
 
 k2
Value: 0.0050   (Units: 1/(nM*hr))
Constant
 
RL-Gprotein association (1)
 
   k3
Value: 0.02   (Units: 1/(nM*hr))
Constant
 
RGabg-Ligand association (1)
 
 k4
Value: 0.0050   (Units: 1/(nM*hr))
Constant
 
Galpha activation by receptor (1)
 
   k5
Value: 50.0   (Units: 1/hr)
Constant
 
Galpha activation spontaneous (1)
 
 k6
Value: 0.2   (Units: 1/hr)
Constant
 
Galpha-RGS association (1)
 
   k7
Value: 500.0   (Units: 1/(nM*hr))
Constant
 
Galpha deactivation by RGS (1)
 
   k8
Value: 2.5   (Units: 1/hr)
Constant
 
Galpha deactivation spontaneous (1)
 
   k9
Value: 0.0050   (Units: 1/hr)
Constant
 
Galpha-Effector association (1)
 
   k10
Value: 10.0   (Units: 1/(nM*hr))
Constant
 
Galpha becomes inert (1)
 
 k11
Value: 1.0   (Units: 1/hr)
Constant
 
inertGalpha-RGS association (1)
 
   k12
Value: 50.0   (Units: 1/(nM*hr))
Constant
 
inertGalpha deactivation by RGS (1)
 
   k13
Value: 0.3   (Units: 1/hr)
Constant
 
inertGalpha deactivation spontaneous (1)
 
   k14
Value: 0.0050   (Units: 1/hr)
Constant
 
Phosphate release (1)
 
   k15
Value: 1000.0   (Units: 1/hr)
Constant
 
Gprotein subunits association (1)
 
   k16
Value: 1000.0   (Units: 1/(nM*hr))
Constant
 
Phosphate degradation (1)
 
   k17
Value: 10.0   (Units: 1/hr)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000439

Curator's comment: (updated: 12 Mar 2013 12:13:08 GMT)

Figure 6c of the reference publication is reproduced. The curation figure is not consistent with that obtained in the paper. This inconsistency is due to way they were generated.

In the paper, for each concentration, a single value was obtained from the integral of the trajectory of species z3 from time=0 to 30. This means, a single value that represents the area under the curve was obtained by transferring and integrating the simulation data to MATLAB. The plots were then drawn by connecting the points (and smoothed lines) using GraphPad Prism.

The curation figure is obtained by doing a parameter scan for RGS against z3, with twelve different concentrations of ligand. The data were obtained by simulating the model using Copsai v4.8 (Build 35). The plot was generated using Gnuplot.
The

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