Potential Role for Combined Subtype-Selective Targeting of M and M 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 MR and MR muscarinic acetylcholine receptor subtypes encoded respectively by and . Activated MR and MR signal via G 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 MR and MR 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 MR and MR activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas MR activation promotes GI neoplasia, MR activation appears protective. In contrast, in murine liver injury models, MR activation promotes and MR activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of MR and MR-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.