BioModels Database logo

BioModels Database

spacer

BIOMD0000000479 - Croft2013 - GPCR-RGS interaction that compartmentalizes RGS activity

 

 |   |   |  Send feedback
Reference Publication
Publication ID: 23900842
Croft W, Hill C, McCann E, Bond M, Esparza-Franco M, Bennett J, Rand D, Davey J, Ladds G.
A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.
J. Biol. Chem. 2013 Sep; 288(38): 27327-27342
From the Division of Biomedical Cell Biology, Warwick Medical School.  [more]
Model
Original Model: BIOMD0000000479.origin
Submitter: Manuel Esparza-Franco
Submission ID: MODEL1305280000
Submission Date: 28 May 2013 10:50:40 UTC
Last Modification Date: 28 Apr 2014 16:04:49 UTC
Creation Date: 13 Sep 2013 12:39:39 UTC
Encoders:  Vijayalakshmi Chelliah
   Manuel Esparza-Franco
   Wayne Croft
set #1
bqmodel:isDerivedFrom BioModels Database Smith2009 - RGS mediated GTP hydrolysis
PubMed 15313578
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
bqbiol:isVersionOf Gene Ontology regulation of GTPase activity
bqbiol:hasTaxon Taxonomy Saccharomyces cerevisiae
Notes
Croft2013 - GPCR-RGS interaction that compartmentalizes RGS activity

Through modelling studies, the classic quaternary complex (ligand-GPCR-G-RGS) has been extended to include an additional layer of regulation through GPCR-RGS interactions, which facilitate the compartmentalization of RGS activity into the plasma membrane and non-plasma compartments.

This model is described in the article:

Croft W, Hill C, McCann E, Bond M, Esparza-Franco M, Bennett J, Rand D, Davey J, Ladds G.
J Biol Chem. 2013 Sep 20;288(38):27327-42.

Abstract:

G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the Gα subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the Gα subunit, a reaction catalyzed by RGS proteins. Using yeast as a tool to study GPCR signaling in isolation, we define an interaction between the cognate GPCR (Mam2) and RGS (Rgs1), mapping the interaction domains. This reaction tethers Rgs1 at the plasma membrane and is essential for physiological signaling response. In vivo quantitative data inform the development of a kinetic model of the GTPase cycle, which extends previous attempts by including GPCR-RGS interactions. In vivo and in silico data confirm that GPCR-RGS interactions can impose an additional layer of regulation through mediating RGS subcellular localization to compartmentalize RGS activity within a cell, thus highlighting their importance as potential targets to modulate GPCR signaling pathways.

Author's comment on reproducing the plots:
To reproduce dose-response plots in the publication, the model is simulated with 12 different ligand concentrations (see parameter Ligand_conc).
For each ligand concentration, a single value corresponding to total amount of output must be obtained, by calculating the area under the curve of the trajectory of species z3, from time=0 to time=30.
These total output 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 specified in the Supplementary Material.

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: 23900842 Submission Date: 28 May 2013 10:50:40 UTC Last Modification Date: 28 Apr 2014 16:04:49 UTC Creation Date: 13 Sep 2013 12:39:39 UTC
Mathematical expressions
Reactions
Receptor-Ligand association Receptor-Gprotein association LR-Gprotein association Ligand-RGabg association
Ligand-RRGSm association RRGSm-Gprotein association LRRGSm-Gprotein association Ligand-RRGSmGabg association
Gprotein activation by LR Gprotein spontaneous activation Gprotein activation by LRRGSm Effector-GaGTP association
RGS in cytosol moves to membrane RGS in membrane moves to cytosol Receptor recruits RGSc to membrane R-RGSm dissociation
LR recruits RGSc to membrane LR-RGSm dissociation RGabg recruits RGSc to membrane RRGSmGabg dissociation
LRGabg recruits RGSc to membrane GaGTP recruits RGSc to membrane RGSmGaGTP dissociation GaGTPEffectorOFF recruits RGS from cytosol
Effector turns off GaGTP hydrolyzes GTP GaGTP-RGSm association RGSmGaGTP hydrolyzes GTP
GaGTP-LRRGSm association LRRGSmGaGTP hydrolyzes GTP GaGTP-RRGSm association RRGSmGaGTP hydrolyzes GTP
GaGTPEffectorOFF hydrolyzes GTP GaGTPEffectorOFF-RGSm association RGSmGaGTPEffectorOFF hydrolyzes GTP GaGTPEffectorOFF-LRRGSm association
LRRGSmGaGTPEffectorOFF hydrolyzes GTP Phosphate release Gprotein subunits association Phosphate degradation
Delay 1 Delay 2 Delay 3 Final output
Events
Ligand_addition      
Physical entities
Compartments Species
cell L R LR
Gabg RGabg LRGabg
RRGSm LRRGSm RRGSmGabg
LRRGSmGabg GaGTP Gbg
Effector GaGTPEffector RGSc
RGSm RGSmGaGTP GaGTPEffectorOFF
RGSmGaGTPEffectorOFF GaGDPP LRRGSmGaGTP
RRGSmGaGTP LRRGSmGaGTPEffectorOFF GaGDP
P z1 z2
z3    
Global parameters
ka Ligand_conc    
Reactions (44)
 
 Receptor-Ligand association [L] + [R] → [LR];   {L} , {R}
 
 Receptor-Gprotein association [R] + [Gabg] → [RGabg];   {R} , {Gabg}
 
 LR-Gprotein association [LR] + [Gabg] → [LRGabg];   {LR} , {Gabg}
 
 Ligand-RGabg association [L] + [RGabg] → [LRGabg];   {L} , {RGabg}
 
 Ligand-RRGSm association [L] + [RRGSm] → [LRRGSm];   {L} , {RRGSm}
 
 RRGSm-Gprotein association [RRGSm] + [Gabg] → [RRGSmGabg];   {RRGSm} , {Gabg}
 
 LRRGSm-Gprotein association [LRRGSm] + [Gabg] → [LRRGSmGabg];   {LRRGSm} , {Gabg}
 
 Ligand-RRGSmGabg association [L] + [RRGSmGabg] → [LRRGSmGabg];   {L} , {RRGSmGabg}
 
 Gprotein activation by LR [LRGabg] → [LR] + [GaGTP] + [Gbg];   {LRGabg}
 
 Gprotein spontaneous activation [Gabg] → [GaGTP] + [Gbg];   {Gabg}
 
 Gprotein activation by LRRGSm [LRRGSmGabg] → [GaGTP] + [Gbg] + [LRRGSm];   {LRRGSmGabg}
 
 Effector-GaGTP association [Effector] + [GaGTP] → [GaGTPEffector];   {Effector} , {GaGTP}
 
 RGS in cytosol moves to membrane [RGSc] → [RGSm];   {RGSc}
 
 RGS in membrane moves to cytosol [RGSm] → [RGSc];   {RGSm}
 
 Receptor recruits RGSc to membrane [R] + [RGSc] → [RRGSm];   {R} , {RGSc}
 
 R-RGSm dissociation [RRGSm] → [R] + [RGSm];   {RRGSm}
 
 LR recruits RGSc to membrane [LR] + [RGSc] → [LRRGSm];   {LR} , {RGSc}
 
 LR-RGSm dissociation [LRRGSm] → [LR] + [RGSm];   {LRRGSm}
 
 RGabg recruits RGSc to membrane [RGabg] + [RGSc] → [RRGSmGabg];   {RGabg} , {RGSc}
 
 RRGSmGabg dissociation [RRGSmGabg] → [RGabg] + [RGSm];   {RRGSmGabg}
 
 LRGabg recruits RGSc to membrane [LRGabg] + [RGSc] → [LRRGSmGabg];   {LRGabg} , {RGSc}
 
 GaGTP recruits RGSc to membrane [GaGTP] + [RGSc] → [RGSmGaGTP];   {GaGTP} , {RGSc}
 
 RGSmGaGTP dissociation [RGSmGaGTP] → [GaGTP] + [RGSc];   {RGSmGaGTP}
 
 GaGTPEffectorOFF recruits RGS from cytosol [GaGTPEffectorOFF] + [RGSc] → [RGSmGaGTPEffectorOFF];   {GaGTPEffectorOFF} , {RGSc}
 
 Effector turns off [GaGTPEffector] → [GaGTPEffectorOFF];   {GaGTPEffector}
 
 GaGTP hydrolyzes GTP [GaGTP] → [GaGDPP];   {GaGTP}
 
 GaGTP-RGSm association [GaGTP] + [RGSm] → [RGSmGaGTP];   {GaGTP} , {RGSm}
 
 RGSmGaGTP hydrolyzes GTP [RGSmGaGTP] → [GaGDPP] + [RGSc];   {RGSmGaGTP}
 
 GaGTP-LRRGSm association [GaGTP] + [LRRGSm] → [LRRGSmGaGTP];   {GaGTP} , {LRRGSm}
 
 LRRGSmGaGTP hydrolyzes GTP [LRRGSmGaGTP] → [GaGDPP] + [LRRGSm];   {LRRGSmGaGTP}
 
 GaGTP-RRGSm association [GaGTP] + [RRGSm] → [RRGSmGaGTP];   {GaGTP} , {RRGSm}
 
 RRGSmGaGTP hydrolyzes GTP [RRGSmGaGTP] → [GaGDPP] + [RRGSm];   {RRGSmGaGTP}
 
 GaGTPEffectorOFF hydrolyzes GTP [GaGTPEffectorOFF] → [GaGDPP] + [Effector];   {GaGTPEffectorOFF}
 
 GaGTPEffectorOFF-RGSm association [GaGTPEffectorOFF] + [RGSm] → [RGSmGaGTPEffectorOFF];   {GaGTPEffectorOFF} , {RGSm}
 
 RGSmGaGTPEffectorOFF hydrolyzes GTP [RGSmGaGTPEffectorOFF] → [GaGDPP] + [RGSc] + [Effector];   {RGSmGaGTPEffectorOFF}
 
 GaGTPEffectorOFF-LRRGSm association [GaGTPEffectorOFF] + [LRRGSm] → [LRRGSmGaGTPEffectorOFF];   {GaGTPEffectorOFF} , {LRRGSm}
 
 LRRGSmGaGTPEffectorOFF hydrolyzes GTP [LRRGSmGaGTPEffectorOFF] → [GaGDPP] + [LRRGSm] + [Effector];   {LRRGSmGaGTPEffectorOFF}
 
 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}
 
 Final output [z3] → ;   {z3}
 
Events (1)
 
 Ligand_addition
L = L+Ligand_conc
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 L
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 R
Compartment: cell
Initial concentration: 205.0  (Units: nanoMolar)
 
 LR
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)
 
 LRGabg
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RRGSm
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 LRRGSm
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RRGSmGabg
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 LRRGSmGabg
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)
 
 Effector
Compartment: cell
Initial concentration: 305.0  (Units: nanoMolar)
 
 GaGTPEffector
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RGSc
Compartment: cell
Initial concentration: 60.0  (Units: nanoMolar)
 
 RGSm
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RGSmGaGTP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 GaGTPEffectorOFF
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RGSmGaGTPEffectorOFF
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 GaGDPP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 LRRGSmGaGTP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 RRGSmGaGTP
Compartment: cell
Initial concentration: 0.0  (Units: nanoMolar)
 
 LRRGSmGaGTPEffectorOFF
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: 0.005   (Units: 1/(nM*hr))
Constant
 
LR-Gprotein association (1)
 
   k3
Value: 0.02   (Units: 1/(nM*hr))
Constant
 
Ligand-RGabg association (1)
 
   k4
Value: 0.005   (Units: 1/(nM*hr))
Constant
 
Ligand-RRGSm association (1)
 
   k5
Value: 0.005   (Units: 1/(nM*hr))
Constant
 
RRGSm-Gprotein association (1)
 
   k6
Value: 0.005   (Units: 1/(nM*hr))
Constant
 
LRRGSm-Gprotein association (1)
 
   k7
Value: 0.02   (Units: 1/(nM*hr))
Constant
 
Ligand-RRGSmGabg association (1)
 
   k8
Value: 0.005   (Units: 1/(nM*hr))
Constant
 
Gprotein activation by LR (1)
 
   k9
Value: 50.0   (Units: 1/hr)
Constant
 
Gprotein spontaneous activation (1)
 
   k10
Value: 0.2   (Units: 1/hr)
Constant
 
Gprotein activation by LRRGSm (1)
 
   k11
Value: 40.0   (Units: 1/hr)
Constant
 
Effector-GaGTP association (1)
 
   k12
Value: 10.0   (Units: 1/(nM*hr))
Constant
 
RGS in cytosol moves to membrane (1)
 
   k13
Value: 5.0E-4   (Units: 1/hr)
Constant
 
RGS in membrane moves to cytosol (1)
 
   k14
Value: 0.005   (Units: 1/hr)
Constant
 
Receptor recruits RGSc to membrane (1)
 
   k15
Value: 0.1   (Units: 1/(nM*hr))
Constant
 
R-RGSm dissociation (1)
 
   k16
Value: 100.0   (Units: 1/hr)
Constant
 
LR recruits RGSc to membrane (1)
 
   k17
Value: 0.1   (Units: 1/(nM*hr))
Constant
 
LR-RGSm dissociation (1)
 
   k18
Value: 100.0   (Units: 1/hr)
Constant
 
RGabg recruits RGSc to membrane (1)
 
   k19
Value: 0.1   (Units: 1/(nM*hr))
Constant
 
RRGSmGabg dissociation (1)
 
   k20
Value: 0.1   (Units: 1/hr)
Constant
 
LRGabg recruits RGSc to membrane (1)
 
   k21
Value: 0.1   (Units: 1/(nM*hr))
Constant
 
GaGTP recruits RGSc to membrane (1)
 
   k22
Value: 60.0   (Units: 1/(nM*hr))
Constant
 
RGSmGaGTP dissociation (1)
 
   k23
Value: 0.05   (Units: 1/hr)
Constant
 
GaGTPEffectorOFF recruits RGS from cytosol (1)
 
   k24
Value: 1.0E-4   (Units: 1/(nM*hr))
Constant
 
Effector turns off (1)
 
   k25
Value: 1.0   (Units: 1/hr)
Constant
 
GaGTP hydrolyzes GTP (1)
 
   k26
Value: 0.005   (Units: 1/hr)
Constant
 
GaGTP-RGSm association (1)
 
   k27
Value: 500.0   (Units: 1/(nM*hr))
Constant
 
RGSmGaGTP hydrolyzes GTP (1)
 
   k28
Value: 2.5   (Units: 1/hr)
Constant
 
GaGTP-LRRGSm association (1)
 
   k29
Value: 100.0   (Units: 1/(nM*hr))
Constant
 
LRRGSmGaGTP hydrolyzes GTP (1)
 
   k30
Value: 2.5   (Units: 1/hr)
Constant
 
GaGTP-RRGSm association (1)
 
   k31
Value: 0.5   (Units: 1/(nM*hr))
Constant
 
RRGSmGaGTP hydrolyzes GTP (1)
 
   k32
Value: 0.5   (Units: 1/hr)
Constant
 
GaGTPEffectorOFF hydrolyzes GTP (1)
 
   k33
Value: 0.005   (Units: 1/hr)
Constant
 
GaGTPEffectorOFF-RGSm association (1)
 
   k34
Value: 50.0   (Units: 1/(nM*hr))
Constant
 
RGSmGaGTPEffectorOFF hydrolyzes GTP (1)
 
   k35
Value: 0.3   (Units: 1/hr)
Constant
 
GaGTPEffectorOFF-LRRGSm association (1)
 
   k36
Value: 50.0   (Units: 1/(nM*hr))
Constant
 
LRRGSmGaGTPEffectorOFF hydrolyzes GTP (1)
 
   k37
Value: 0.3   (Units: 1/hr)
Constant
 
Phosphate release (1)
 
   k38
Value: 1000.0   (Units: 1/hr)
Constant
 
Gprotein subunits association (1)
 
   k39
Value: 1000.0   (Units: 1/(nM*hr))
Constant
 
Phosphate degradation (1)
 
   k40
Value: 10.0   (Units: 1/hr)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000479

Curator's comment: (updated: 13 Sep 2013 13:38:39 BST)

Figure 8A of the corresponding publication has been reproduced by varying RGSc values as displayed in the figure legend. The simulation was doing using Copasi v4.10 (Build 55). The plot was generated using Gnuplot.

spacer
spacer