Dataset Information

Smith2009 - RGS mediated GTP hydrolysis

ABSTRACT: 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 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.

SUBMITTER: Manuel Esparza-Franco

PROVIDER: BIOMD0000000439 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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	BIOMD0000000439?filename=BIOMD0000000439-biopax3.owl	Owl
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Dual positive and negative regulation of GPCR signaling by GTP hydrolysis.

Smith Benjamin B Hill Claire C Godfrey Emma L EL Rand David D van den Berg Hugo H Thornton Steven S Hodgkin Matthew M Davey John J Ladds Graham G

Cellular signalling 20090312 7

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) respon ...[more]

PMID: 19285552

Publication: 1/2

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Project description: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: A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity. 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. This model is hosted on BioModels Database and identified by: BIOMD0000000479 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . 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.

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