Muscarinic acetylcholine receptor M2 (M2R) (M2R)

The Muscarinic acetylcholine receptor M2 (M2R) is a Class A G protein-coupled receptor (GPCR) encoded by the CHRM2 gene, primarily signaling through the Gi/o heterotrimeric G proteins to inhibit adenylate cyclase and activate G protein-gated inwardly rectifying potassium (GIRK) channels [1, 2]. It is most prominently expressed in the heart, specifically in the sinoatrial and atrioventricular nodes, where it mediates the vagal (parasympathetic) slowing of the heart rate and conduction velocity [3]. In the central nervous system, M2R acts as a presynaptic autoreceptor that inhibits the release of acetylcholine, thereby playing a critical role in modulating cognitive functions, memory, and thermoregulation [1, 4]. Pathologically, M2R dysfunction is linked to cardiovascular disorders like sinus bradycardia and atrial fibrillation, as well as neurological and psychiatric conditions including Alzheimer's disease and depression [2, 4]. Therapeutic interventions include non-selective antagonists like atropine for treating symptomatic bradycardia and selective research tools like methoctramine, though clinical use is often limited by lack of subtype selectivity across the M1-M5 family [2, 3]. The receptor's structure features a deep orthosteric binding pocket for acetylcholine and an extracellular allosteric site that has become a major focus for drug discovery to achieve better subtype specificity [4].

Other names

CHRM2Cholinergic receptor muscarinic 2M2 muscarinic receptorMuscarinic acetylcholine receptor 2

The M2 receptor primarily signals through Gi/o proteins to inhibit adenylyl cyclase, reducing cAMP levels, and activates G protein-gated inwardly rectifying potassium (GIRK) channels, leading to cellular hyperpolarization [1, 2]. It also inhibits voltage-gated calcium channels, further modulating cellular excitability and neurotransmitter release [4].