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

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 vari...

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Autores principales: Onfroy, Lauriane, Galandrin, Ségolène, Pontier, Stéphanie M., Seguelas, Marie-Hélène, N’Guyen, Du, Sénard, Jean-Michel, Galés, Céline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554226/
https://www.ncbi.nlm.nih.gov/pubmed/28801617
http://dx.doi.org/10.1038/s41598-017-07392-5
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author Onfroy, Lauriane
Galandrin, Ségolène
Pontier, Stéphanie M.
Seguelas, Marie-Hélène
N’Guyen, Du
Sénard, Jean-Michel
Galés, Céline
author_facet Onfroy, Lauriane
Galandrin, Ségolène
Pontier, Stéphanie M.
Seguelas, Marie-Hélène
N’Guyen, Du
Sénard, Jean-Michel
Galés, Céline
author_sort Onfroy, Lauriane
collection PubMed
description 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.
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spelling pubmed-55542262017-08-15 G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning Onfroy, Lauriane Galandrin, Ségolène Pontier, Stéphanie M. Seguelas, Marie-Hélène N’Guyen, Du Sénard, Jean-Michel Galés, Céline Sci Rep Article 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. Nature Publishing Group UK 2017-08-11 /pmc/articles/PMC5554226/ /pubmed/28801617 http://dx.doi.org/10.1038/s41598-017-07392-5 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Onfroy, Lauriane
Galandrin, Ségolène
Pontier, Stéphanie M.
Seguelas, Marie-Hélène
N’Guyen, Du
Sénard, Jean-Michel
Galés, Céline
G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554226/
https://www.ncbi.nlm.nih.gov/pubmed/28801617
http://dx.doi.org/10.1038/s41598-017-07392-5
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