Muscarinic acetylcholine receptor M1; Muscarinic acetylcholine receptor M2 (M1, M2)

Muscarinic acetylcholine receptors M1 and M2 are members of the G protein-coupled receptor (GPCR) superfamily, activated by the endogenous neurotransmitter acetylcholine. The M1 receptor (M1; Cholinergic receptor muscarinic M1) is primarily expressed in the central nervous system, particularly in regions involved in learning and memory, and is a major target for Alzheimer’s disease and other cognitive disorders[1][2][3][4][6]. The M2 receptor (M2; Cholinergic receptor muscarinic M2) is most abundant in cardiac tissue, where it mediates slowing of heart rate and plays a pivotal role in parasympathetic control of the heart[1][7][9]. Both receptors activate distinct G proteins (Gq/11 for M1, Gi/o for M2) and elicit opposing cellular effects—excitatory for M1 and inhibitory for M2. They are intensively studied as drug targets, but the clinical utility of selective muscarinic modulators has been limited due to the high homology of their acetylcholine-binding pockets and the associated peripheral side effects of non-selective agents[2][4][9]. Ongoing research aims to develop subtype-selective orthosteric and allosteric modulators to treat neurological, psychiatric, and cardiovascular diseases with improved safety profiles[3][4][9].

Other names

M1 receptorM2 receptormAChR M1mAChR M2Cholinergic receptor muscarinic M1Cholinergic receptor muscarinic M2

Agonists: Activate the receptor, mimicking acetylcholine to trigger downstream G protein signaling (M1 via Gq/11, M2 via Gi/o) Antagonists: Block acetylcholine binding, inhibiting downstream signaling Positive allosteric modulators: Bind to sites distinct from acetylcholine site, enhancing receptor response Inverse agonists: Stabilize inactive conformation, reducing baseline activity