Potential Role for Combined Subtype-Selective Targeting of M(1) and M(3) 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 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.