Muscarinic acetylcholine receptor M2 (CHRM2) (CHRM2)

The Muscarinic acetylcholine receptor M2 is a G protein-coupled receptor (GPCR) predominantly found in the heart, smooth muscle, and central nervous system (UniProt) [11, 12]. In cardiac tissue, it mediates the parasympathetic effects of acetylcholine, primarily acting to decrease heart rate (negative chronotropy) and reduce conduction velocity through the atrioventricular node by coupling with Gi/o proteins to inhibit adenylyl cyclase and activate inwardly-rectifying potassium channels (Wikipedia) [4, 10, 16]. Beyond its cardiac role, the receptor acts as a presynaptic autoreceptor in the brain, regulating the release of acetylcholine and thereby influencing cognitive processes, thermoregulation, and pain perception (PubMed) [14, 17]. Dysregulation of M2 receptor signaling is implicated in a broad range of pathologies, including bradyarrhythmias, heart failure, Alzheimer's disease, and overactive bladder (NIH) [5, 13, 21]. Consequently, this receptor is a significant therapeutic target across multiple specialties; antagonists are used for respiratory and urological conditions, while agonists and allosteric modulators are explored for their potential in managing cardiovascular and neurological disorders (GlobalData) [2, 6, 18]. Medicinal compounds targeting this receptor range from non-selective antagonists like atropine to subtype-selective allosteric modulators currently in clinical development (ResearchGate) [6, 18].

Other names

Cholinergic receptor muscarinic 2M2 receptorHM2Muscarinic-2 receptorM2 muscarinic receptorAcetylcholine receptor M2

Drugs targeting the M2 receptor act as orthosteric agonists, antagonists, or allosteric modulators. Agonists bind the receptor to activate Gi/o protein signaling, which inhibits adenylyl cyclase (decreasing intracellular cAMP) and activates G protein-coupled inwardly-rectifying potassium channels, resulting in inhibitory physiological effects such as heart rate slowing (StatPearls) [9, 10]. Antagonists competitively block acetylcholine binding at the orthosteric site to prevent these parasympathetic effects, thereby increasing heart rate or facilitating smooth muscle relaxation in the lungs and bladder (IUPHAR) [8, 10, 13]. Positive allosteric modulators (PAMs) bind to a distinct site to enhance the receptor's sensitivity to endogenous acetylcholine, providing a mechanism to selectively increase parasympathetic tone in conditions like heart failure (ResearchGate) [6].