Muscarinic acetylcholine receptor M1, M4, and M5 (mAChR M1/M4/M5)

The peripheral muscarinic acetylcholine receptors M1, M4, and M5 are G protein-coupled receptors that mediate the effects of acetylcholine in tissues outside the central nervous system. While these subtypes are primarily recognized for their roles in the brain—where M1 and M4 are major targets for treating schizophrenia and cognitive disorders—they are also present in various peripheral organs. M1 receptors are found in autonomic ganglia and secretory glands, M4 receptors are expressed in the lungs and skin, and M5 receptors are located in the vascular endothelium. Activation of these peripheral receptors by non-selective muscarinic agonists, such as xanomeline, leads to significant side effects including nausea, vomiting, salivation, and diaphoresis. Consequently, therapeutic strategies like the combination of xanomeline and trospium (KarXT) utilize peripheral muscarinic antagonists to block these receptors and improve tolerability. Trospium chloride, a peripherally restricted antagonist, prevents the activation of these receptors without interfering with the desired central effects of the agonist. Understanding the peripheral distribution and function of M1, M4, and M5 is essential for developing selective therapies that maximize central nervous system benefits while minimizing systemic toxicity. These receptors also play roles in physiological processes such as gastric acid secretion and vasodilation, making them relevant in various disease states. Overall, the peripheral population of M1, M4, and M5 receptors represents a critical consideration in the safety and efficacy of muscarinic-based drug development.

Other names

CHRM1CHRM4CHRM5Muscarinic receptor subtypes 1, 4, and 5Peripheral muscarinic receptors

Agonism of central M1 and M4 receptors for therapeutic effect; Antagonism of peripheral M1, M4, and M5 receptors to mitigate side effects.