Muscarinic acetylcholine receptor M2-M5 (CHRM2-5) (CHRM2-5)

The muscarinic acetylcholine receptors M2 through M5 (CHRM2–CHRM5) are a group of G protein-coupled receptors (GPCRs) that mediate the metabotropic actions of acetylcholine in the central and peripheral nervous systems [StatPearls: Physiology, Muscarinic Receptors]. The M2 and M4 subtypes are primarily coupled to Gi/o proteins, which inhibit adenylyl cyclase and decrease cAMP levels; M2 is notably found in the heart where it slows the heart rate, while M4 is highly expressed in the striatum and is a target for antipsychotic research [UniProt P08172, P08173]. The M3 and M5 subtypes are coupled to Gq/11 proteins, activating phospholipase C and increasing intracellular calcium to drive smooth muscle contraction, glandular secretion, and vasodilation [UniProt P20366, P08912]. Clinically, these receptors are targeted by a variety of drugs: M3 antagonists like tiotropium and oxybutynin are used for respiratory and urinary disorders, respectively, while M2/M4 pathways are explored for treating neurodegenerative and psychiatric conditions [IUPHAR Guide to Pharmacology]. A significant challenge in targeting these receptors is their high sequence homology, which often results in poor subtype selectivity and leads to common side effects such as dry mouth, blurred vision, and tachycardia [PubMed: PMC7070169].

Other names

mAChR M2-M5Cholinergic receptor muscarinic 2-5CHRM2CHRM3CHRM4CHRM5

Muscarinic M2 and M4 receptors act via Gi-type G proteins to inhibit adenylyl cyclase, while M3 and M5 receptors act via Gq-type G proteins to stimulate phospholipase C and increase intracellular calcium [StatPearls: Physiology, Muscarinic Receptors]. Drugs targeting these receptors act as either agonists to mimic acetylcholine or antagonists to competitively block its binding, thereby modulating autonomic functions like heart rate and smooth muscle tone or central functions like cognition and motor control [IUPHAR Guide to Pharmacology].