Muscarinic acetylcholine receptor M2; Muscarinic acetylcholine receptor M3 (M2 receptor; M3 receptor)

Muscarinic acetylcholine receptor M2 and M3 are two subtypes of the muscarinic receptor family, which belong to the class A G protein-coupled receptor (GPCR) superfamily. M2 is primarily expressed in the heart, where it mediates the parasympathetic inhibition of cardiac activity (slows heart rate and reduces atrial contractility) through coupling to Gi/o proteins, leading to decreased cAMP production. M3 is found mainly in smooth muscle and glandular tissues, mediating contraction and secretion respectively, by signaling through Gq/11 proteins to increase intracellular calcium. Both receptors are involved in numerous physiological processes and are established therapeutic targets in the treatment of conditions such as COPD, asthma, overactive bladder, and, experimentally, neuropsychiatric disorders such as schizophrenia. The recent elucidation of their high-resolution structures has enabled the design of more selective drugs, including bitopic and allosteric modulators, though achieving clinically meaningful subtype selectivity remains challenging due to their high sequence similarity in ligand binding domains[1][2][3][4][5][7][9][10].

Other names

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

Agonists activate the receptor, mimicking acetylcholine to induce parasympathetic effects (e.g., bradycardia for M2, smooth muscle contraction for M3). Antagonists block acetylcholine binding, inhibiting receptor-mediated effects (e.g., bronchodilation by M3 antagonism in asthma/COPD). Allosteric modulators bind to sites distinct from the orthosteric acetylcholine site, modulating receptor activity and selectivity. Bitopic ligands bridge orthosteric and allosteric sites for increased selectivity and/or efficacy.