Muscarinic acetylcholine receptor M2 and Muscarinic acetylcholine receptor M3 (M2 and M3)

Muscarinic acetylcholine receptors M2 and M3 are members of the G protein-coupled receptor superfamily that respond to the neurotransmitter acetylcholine. M2 receptors are primarily found in the heart, where they mediate inhibitory effects on cardiac function predominantly via Gi/o protein coupling, decreasing heart rate and contractility. M3 receptors are located on smooth muscle and glandular tissue, mediating contraction, secretion, and vasodilation (via endothelial nitric oxide release) through Gq/11 protein signaling, increasing intracellular calcium levels. Both are critical for the function of the parasympathetic nervous system, and their modulation has therapeutic applications in treating conditions such as chronic obstructive pulmonary disease (COPD), overactive bladder, and certain neuropsychiatric disorders. Structural characterization of these receptors in various conformations has informed drug discovery efforts for selective ligands, but clinical selectivity remains a challenge due to high sequence similarity in the orthosteric binding sites.

Other names

M2 muscarinic receptorM3 muscarinic receptorCholinergic receptor muscarinic 2Cholinergic receptor muscarinic 3mAChR M2mAChR M3

Orthosteric antagonism: blocks acetylcholine binding at the classical ligand site (e.g., tiotropium, ipratropium, darifenacin); Allosteric modulation: drugs bind a secondary site, altering receptor activity without blocking acetylcholine directly (under research, especially for M2); Bitopic modulation: drugs bridge both allosteric and orthosteric sites (in research, e.g., THRX-160209 for M2); Orthosteric agonism: mimics acetylcholine at the receptor (e.g., xanomeline)