Potential Role for Combined Subtype-Selective Targeting of M 1 and M 3 Muscarinic Receptors in Gastrointestinal and Liver Diseases.

Autor: Tolaymat M; Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States., Sundel MH; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States., Alizadeh M; Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States., Xie G; Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States.; VA Maryland Healthcare System, Baltimore, MD, United States.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States., Raufman JP; Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States.; VA Maryland Healthcare System, Baltimore, MD, United States.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States.; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United States.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2021 Nov 04; Vol. 12, pp. 786105. Date of Electronic Publication: 2021 Nov 04 (Print Publication: 2021).
DOI: 10.3389/fphar.2021.786105
Abstrakt: 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 M 1 R and M 3 R muscarinic acetylcholine receptor subtypes encoded respectively by CHRM1 and CHRM3 . Activated M 1 R and M 3 R signal via G q 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 M 1 R and M 3 R 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 M 1 R and M 3 R activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas M 3 R activation promotes GI neoplasia, M 1 R activation appears protective. In contrast, in murine liver injury models, M 3 R activation promotes and M 1 R activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of M 1 R and M 3 R-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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Tolaymat, Sundel, Alizadeh, Xie and Raufman.)
Databáze: MEDLINE
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