Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases

Despite structural similarity, the five subtypes comprising the cholinergic muscarinic family of G protein-coupled receptors regulate remarkably diverse biological functions. This mini review focuses on the closely related and commonly co-expressed M1R and M3R muscarinic acetylcholine receptor subty...

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Autores principales:	Mazen Tolaymat, Margaret H. Sundel, Madeline Alizadeh, Guofeng Xie, Jean-Pierre Raufman
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	muscarinic receptors G protein-coupled receptors gastrointestinal physiology gastrointestinal disease liver disease cancer Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/4ccf533168e34682a4486d0d353b67bb
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spelling	oai:doaj.org-article:4ccf533168e34682a4486d0d353b67bb2021-11-04T07:30:25ZPotential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases1663-981210.3389/fphar.2021.786105https://doaj.org/article/4ccf533168e34682a4486d0d353b67bb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.786105/fullhttps://doaj.org/toc/1663-9812Despite structural similarity, the five subtypes comprising the cholinergic muscarinic family of G protein-coupled receptors regulate remarkably diverse biological functions. This mini review focuses on the closely related and commonly co-expressed M1R and M3R muscarinic acetylcholine receptor subtypes encoded respectively by CHRM1 and CHRM3. Activated M1R and M3R signal via Gq and downstream initiate phospholipid turnover, changes in cell calcium levels, and activation of protein kinases that alter gene transcription and ultimately cell function. The unexpectedly divergent effects of M1R and M3R activation, despite similar receptor structure, distribution, and signaling, are puzzling. To explore this conundrum, we focus on the gastrointestinal (GI) tract and liver because abundant data identify opposing effects of M1R and M3R activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas M3R activation promotes GI neoplasia, M1R activation appears protective. In contrast, in murine liver injury models, M3R activation promotes and M1R activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of M1R and M3R-selective agonists and antagonists. We conclude by considering gaps in knowledge and other factors that hinder the application of these drugs and the development of new agents to treat GI and liver diseases.Mazen TolaymatMargaret H. SundelMadeline AlizadehGuofeng XieGuofeng XieGuofeng XieJean-Pierre RaufmanJean-Pierre RaufmanJean-Pierre RaufmanJean-Pierre RaufmanFrontiers Media S.A.articlemuscarinic receptorsG protein-coupled receptorsgastrointestinal physiologygastrointestinal diseaseliver diseasecancerTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	muscarinic receptors G protein-coupled receptors gastrointestinal physiology gastrointestinal disease liver disease cancer Therapeutics. Pharmacology RM1-950
spellingShingle	muscarinic receptors G protein-coupled receptors gastrointestinal physiology gastrointestinal disease liver disease cancer Therapeutics. Pharmacology RM1-950 Mazen Tolaymat Margaret H. Sundel Madeline Alizadeh Guofeng Xie Guofeng Xie Guofeng Xie Jean-Pierre Raufman Jean-Pierre Raufman Jean-Pierre Raufman Jean-Pierre Raufman Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases
description	Despite structural similarity, the five subtypes comprising the cholinergic muscarinic family of G protein-coupled receptors regulate remarkably diverse biological functions. This mini review focuses on the closely related and commonly co-expressed M1R and M3R muscarinic acetylcholine receptor subtypes encoded respectively by CHRM1 and CHRM3. Activated M1R and M3R signal via Gq and downstream initiate phospholipid turnover, changes in cell calcium levels, and activation of protein kinases that alter gene transcription and ultimately cell function. The unexpectedly divergent effects of M1R and M3R activation, despite similar receptor structure, distribution, and signaling, are puzzling. To explore this conundrum, we focus on the gastrointestinal (GI) tract and liver because abundant data identify opposing effects of M1R and M3R activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas M3R activation promotes GI neoplasia, M1R activation appears protective. In contrast, in murine liver injury models, M3R activation promotes and M1R activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of M1R and M3R-selective agonists and antagonists. We conclude by considering gaps in knowledge and other factors that hinder the application of these drugs and the development of new agents to treat GI and liver diseases.
format	article
author	Mazen Tolaymat Margaret H. Sundel Madeline Alizadeh Guofeng Xie Guofeng Xie Guofeng Xie Jean-Pierre Raufman Jean-Pierre Raufman Jean-Pierre Raufman Jean-Pierre Raufman
author_facet	Mazen Tolaymat Margaret H. Sundel Madeline Alizadeh Guofeng Xie Guofeng Xie Guofeng Xie Jean-Pierre Raufman Jean-Pierre Raufman Jean-Pierre Raufman Jean-Pierre Raufman
author_sort	Mazen Tolaymat
title	Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases
title_short	Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases
title_full	Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases
title_fullStr	Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases
title_full_unstemmed	Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases
title_sort	potential role for combined subtype-selective targeting of m1 and m3 muscarinic receptors in gastrointestinal and liver diseases
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/4ccf533168e34682a4486d0d353b67bb
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Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases

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