Muscarinic acetylcholine receptor M2 and Muscarinic acetylcholine receptor M4 (M2/M4)

Muscarinic acetylcholine receptors M2 and M4 are G protein-coupled receptors that mediate many of the effects of acetylcholine in the parasympathetic nervous system.[1][6][7] M2 receptors are predominantly found in the heart, where they regulate heart rate and atrioventricular conduction by inhibiting adenylate cyclase through Gi/o proteins, and are also present in smooth muscle of the airways inhibiting relaxation, and in the central nervous system. M4 receptors are mainly expressed in the central nervous system, particularly in the striatum, and modulate neurotransmitter release and are implicated in regulating movement, cognition, and behavior.[1][6][7][5] Both receptors are central to drug development for neurological and psychiatric diseases, as well as cardiovascular conditions. Drugs targeting these receptors include both agonists and antagonists, with recent breakthroughs in selective agonists for conditions like schizophrenia (e.g., xanomeline-trospium combination, KarXT)[5]. Off-target and systemic effects, especially anticholinergic burdens, remain a therapeutic challenge.

Other names

M2cholinergic receptor, muscarinic 2M4cholinergic receptor, muscarinic 4mAChR M2mAChR M4Muscarinic receptor M2Muscarinic receptor M4

Agonists stimulate the receptor, mimicking acetylcholine and activating downstream G protein signaling (Gi/o coupling: inhibits adenylate cyclase, lowers cAMP) - Antagonists block acetylcholine binding, inhibiting receptor-mediated physiological responses - Allosteric modulators alter receptor function by binding to sites distinct from the primary acetylcholine binding pocket