Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses – termed bias – potentially by eliciting different levels of recruitment of effector pro...

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Autores principales:	Anja Floeser, Katharina Becker, Evi Kostenis, Gabriele König, Cornelius Krasel, Peter Kolb, Moritz Buenemann
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	G protein-coupled receptors receptor conformations biased agonist FRET recruitment bias Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/55dbf4c464dd4abe9df616fac7e0a3e8
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id	oai:doaj.org-article:55dbf4c464dd4abe9df616fac7e0a3e8
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spelling	oai:doaj.org-article:55dbf4c464dd4abe9df616fac7e0a3e82021-12-01T16:50:53ZDisentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor10.7554/eLife.584422050-084Xe58442https://doaj.org/article/55dbf4c464dd4abe9df616fac7e0a3e82021-12-01T00:00:00Zhttps://elifesciences.org/articles/58442https://doaj.org/toc/2050-084XG protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses – termed bias – potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct.Anja FloeserKatharina BeckerEvi KostenisGabriele KönigCornelius KraselPeter KolbMoritz BuenemanneLife Sciences Publications LtdarticleG protein-coupled receptorsreceptor conformationsbiased agonistFRETrecruitment biasMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	G protein-coupled receptors receptor conformations biased agonist FRET recruitment bias Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	G protein-coupled receptors receptor conformations biased agonist FRET recruitment bias Medicine R Science Q Biology (General) QH301-705.5 Anja Floeser Katharina Becker Evi Kostenis Gabriele König Cornelius Krasel Peter Kolb Moritz Buenemann Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor
description	G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses – termed bias – potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct.
format	article
author	Anja Floeser Katharina Becker Evi Kostenis Gabriele König Cornelius Krasel Peter Kolb Moritz Buenemann
author_facet	Anja Floeser Katharina Becker Evi Kostenis Gabriele König Cornelius Krasel Peter Kolb Moritz Buenemann
author_sort	Anja Floeser
title	Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor
title_short	Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor
title_full	Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor
title_fullStr	Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor
title_full_unstemmed	Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor
title_sort	disentangling bias between gq, grk2, and arrestin3 recruitment to the m3 muscarinic acetylcholine receptor
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/55dbf4c464dd4abe9df616fac7e0a3e8
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_version_	1718404750778564608

Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor

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