Muscarinic acetylcholine receptors M2, M3, and M5 (CHRM2, CHRM3, CHRM5)

Muscarinic acetylcholine receptors M2, M3, and M5 are G protein-coupled receptors (GPCRs) that mediate the diverse physiological effects of acetylcholine in the central and peripheral nervous systems [16, 20]. These subtypes are distinguished by their primary G protein coupling: M2 is Gi/o-coupled, leading to inhibitory effects such as slowing the heart rate and presynaptic inhibition, whereas M3 and M5 are Gq/11-coupled, stimulating the phospholipase C pathway to increase intracellular calcium [15, 19, 20]. M2 receptors are predominantly found in the heart and brain, regulating cardiac rhythm and cognitive processes [16, 25]. M3 receptors are widely expressed in smooth muscles and exocrine glands, where they control contraction (e.g., in the bladder and airways) and secretion (e.g., saliva and gastric acid) [17, 19, 21]. M5 receptors are primarily localized in the brain, particularly in the substantia nigra and ventral tegmental area, where they regulate dopaminergic neurotransmission and cerebral blood flow [15, 18, 20]. Drugs targeting these receptors include antagonists like tiotropium for COPD and darifenacin for overactive bladder, as well as agonists being explored for neurological disorders [12, 21, 24]. However, the lack of high subtype selectivity often results in systemic side effects, such as dry mouth, tachycardia, and cognitive dysfunction [21, 23].

Other names

CHRM2CHRM3CHRM5M2 muscarinic receptorM3 muscarinic receptorM5 muscarinic receptorCholinergic receptor muscarinic 2Cholinergic receptor muscarinic 3Cholinergic receptor muscarinic 5Muscarinic acetylcholine receptor subtypes 2, 3, and 5

Drugs targeting these receptors act as orthosteric agonists, competitive antagonists, or allosteric modulators. M2 receptors couple to Gi/o proteins to inhibit adenylate cyclase, while M3 and M5 receptors couple to Gq/11 proteins to activate phospholipase C and increase intracellular calcium [15, 19, 20].