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GPCR endocytosis confers uniformity in responses to chemically distinct ligands

ABSTRACT: This study shows that chemically and pharmacodynamically distinct agonists acting on the same GPCR can produce indistinguishable cellular responses and that this uniformity is conferred by endosomal signaling The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications but, if excessively propagated downstream, would introduce biological 'noise' compromising cognate ligand detection We asked if cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse β-adrenoceptor agonists, isoproterenol and salmeterol We show that both ligands generate an identical integrated response, and that this stereotyped output requires endocytosis We further demonstrate that the endosomal β2-AR signal confers uniformity on the downstream response because it is highly sensitive and saturable Based on these findings, we propose that GPCR signaling from endosomes functions as a biological noise filter to enhance reliability of cognate ligand detection

ORGANISM(S): Homo sapiens

PROVIDER: GSE87461 | GEO | 2016/11/30

SECONDARY ACCESSION(S): PRJNA344802

REPOSITORIES: GEO

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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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GPCR endocytosis confers uniformity in responses to chemically distinct ligands

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