G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning

Abstract Biased agonism at G protein coupled receptors emerges as an opportunity for development of drugs with enhanced benefit/risk balance making biased ligand identification a priority. However, ligand biased signature, classically inferred from ligand activity across multiple pathways, displays...

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Autores principales:	Lauriane Onfroy, Ségolène Galandrin, Stéphanie M. Pontier, Marie-Hélène Seguelas, Du N’Guyen, Jean-Michel Sénard, Céline Galés
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/46b62063d1b048b08dc910da43acf68d
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spelling	oai:doaj.org-article:46b62063d1b048b08dc910da43acf68d2021-12-02T15:05:20ZG protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning10.1038/s41598-017-07392-52045-2322https://doaj.org/article/46b62063d1b048b08dc910da43acf68d2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07392-5https://doaj.org/toc/2045-2322Abstract Biased agonism at G protein coupled receptors emerges as an opportunity for development of drugs with enhanced benefit/risk balance making biased ligand identification a priority. However, ligand biased signature, classically inferred from ligand activity across multiple pathways, displays high variability in recombinant systems. Functional assays usually necessity receptor/effector overexpression that should be controlled among assays to allow comparison but this calibration currently fails. Herein, we demonstrate that Gα expression level dictates the biased profiling of agonists and, to a lesser extent of β-blockers, in a Gα isoform- and receptor-specific way, depending on specific G protein activity in different membrane territories. These results have major therapeutic implications since they suggest that the ligand bias phenotype is not necessarily maintained in pathological cell background characterized by fluctuations in G protein expression. Thus, we recommend implementation of G protein stoichiometry as a new parameter in biased ligand screening programs.Lauriane OnfroySégolène GalandrinStéphanie M. PontierMarie-Hélène SeguelasDu N’GuyenJean-Michel SénardCéline GalésNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lauriane Onfroy Ségolène Galandrin Stéphanie M. Pontier Marie-Hélène Seguelas Du N’Guyen Jean-Michel Sénard Céline Galés G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning
description	Abstract Biased agonism at G protein coupled receptors emerges as an opportunity for development of drugs with enhanced benefit/risk balance making biased ligand identification a priority. However, ligand biased signature, classically inferred from ligand activity across multiple pathways, displays high variability in recombinant systems. Functional assays usually necessity receptor/effector overexpression that should be controlled among assays to allow comparison but this calibration currently fails. Herein, we demonstrate that Gα expression level dictates the biased profiling of agonists and, to a lesser extent of β-blockers, in a Gα isoform- and receptor-specific way, depending on specific G protein activity in different membrane territories. These results have major therapeutic implications since they suggest that the ligand bias phenotype is not necessarily maintained in pathological cell background characterized by fluctuations in G protein expression. Thus, we recommend implementation of G protein stoichiometry as a new parameter in biased ligand screening programs.
format	article
author	Lauriane Onfroy Ségolène Galandrin Stéphanie M. Pontier Marie-Hélène Seguelas Du N’Guyen Jean-Michel Sénard Céline Galés
author_facet	Lauriane Onfroy Ségolène Galandrin Stéphanie M. Pontier Marie-Hélène Seguelas Du N’Guyen Jean-Michel Sénard Céline Galés
author_sort	Lauriane Onfroy
title	G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning
title_short	G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning
title_full	G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning
title_fullStr	G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning
title_full_unstemmed	G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning
title_sort	g protein stoichiometry dictates biased agonism through distinct receptor-g protein partitioning
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/46b62063d1b048b08dc910da43acf68d
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G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning

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