Dataset Information

Bush2016 - Extended Carrousel model of GPCR-RGS

ABSTRACT: Bush2016 - Extended Carrousel model of GPCR-RGS This model is described in the article: Yeast GPCR signaling reflects the fraction of occupied receptors, not the number. Bush A, Vasen G, Constantinou A, Dunayevich P, Patop IL, Blaustein M, Colman-Lerner A. Mol. Syst. Biol. 2016 Dec; 12(12): 898 Abstract: According to receptor theory, the effect of a ligand depends on the amount of agonist-receptor complex. Therefore, changes in receptor abundance should have quantitative effects. However, the response to pheromone in Saccharomyces cerevisiae is robust (unaltered) to increases or reductions in the abundance of the G-protein-coupled receptor (GPCR), Ste2, responding instead to the fraction of occupied receptor. We found experimentally that this robustness originates during G-protein activation. We developed a complete mathematical model of this step, which suggested the ability to compute fractional occupancy depends on the physical interaction between the inhibitory regulator of G-protein signaling (RGS), Sst2, and the receptor. Accordingly, replacing Sst2 by the heterologous hsRGS4, incapable of interacting with the receptor, abolished robustness. Conversely, forcing hsRGS4:Ste2 interaction restored robustness. Taken together with other results of our work, we conclude that this GPCR pathway computes fractional occupancy because ligand-bound GPCR-RGS complexes stimulate signaling while unoccupied complexes actively inhibit it. In eukaryotes, many RGSs bind to specific GPCRs, suggesting these complexes with opposing activities also detect fraction occupancy by a ratiometric measurement. Such complexes operate as push-pull devices, which we have recently described. This model is hosted on BioModels Database and identified by: BIOMD0000000638. 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.

SUBMITTER: Alan Bush

PROVIDER: BIOMD0000000638 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000638?filename=BIOMD0000000638-biopax2.owl	Owl
	BIOMD0000000638?filename=BIOMD0000000638-biopax3.owl	Owl
	BIOMD0000000638?filename=BIOMD0000000638.m	Other
	BIOMD0000000638?filename=BIOMD0000000638.png	Other
	BIOMD0000000638?filename=BIOMD0000000638.sci	Other

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Publications

Yeast GPCR signaling reflects the fraction of occupied receptors, not the number.

Bush Alan A Vasen Gustavo G Constantinou Andreas A Dunayevich Paula P Patop Inés Lucía IL Blaustein Matías M Colman-Lerner Alejandro A

Molecular systems biology 20161229 12

According to receptor theory, the effect of a ligand depends on the amount of agonist-receptor complex. Therefore, changes in receptor abundance should have quantitative effects. However, the response to pheromone in Saccharomyces cerevisiae is robust (unaltered) to increases or reductions in the abundance of the G-protein-coupled receptor (GPCR), Ste2, responding instead to the fraction of occupied receptor. We found experimentally that this robustness originates during G-protein activation. We ...[more]

PMID: 28034910

Publication: 1/15

Similar Datasets

Project description:Bush2016 - Simplified Carrousel model of GPCR This model is described in the article: Yeast GPCR signaling reflects the fraction of occupied receptors, not the number. Bush A, Vasen G, Constantinou A, Dunayevich P, Patop IL, Blaustein M, Colman-Lerner A. Mol. Syst. Biol. 2016 Dec; 12(12): 898 Abstract: According to receptor theory, the effect of a ligand depends on the amount of agonist-receptor complex. Therefore, changes in receptor abundance should have quantitative effects. However, the response to pheromone in Saccharomyces cerevisiae is robust (unaltered) to increases or reductions in the abundance of the G-protein-coupled receptor (GPCR), Ste2, responding instead to the fraction of occupied receptor. We found experimentally that this robustness originates during G-protein activation. We developed a complete mathematical model of this step, which suggested the ability to compute fractional occupancy depends on the physical interaction between the inhibitory regulator of G-protein signaling (RGS), Sst2, and the receptor. Accordingly, replacing Sst2 by the heterologous hsRGS4, incapable of interacting with the receptor, abolished robustness. Conversely, forcing hsRGS4:Ste2 interaction restored robustness. Taken together with other results of our work, we conclude that this GPCR pathway computes fractional occupancy because ligand-bound GPCR-RGS complexes stimulate signaling while unoccupied complexes actively inhibit it. In eukaryotes, many RGSs bind to specific GPCRs, suggesting these complexes with opposing activities also detect fraction occupancy by a ratiometric measurement. Such complexes operate as push-pull devices, which we have recently described. This model is hosted on BioModels Database and identified by: BIOMD0000000637. 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.

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.