Muscarinic acetylcholine receptors M2, M4, M5 (M2R, M4R, M5R)

The muscarinic acetylcholine receptors M2, M4, and M5 are a subset of the five muscarinic receptor subtypes (M1-M5) that mediate the metabotropic actions of acetylcholine in the central and peripheral nervous systems. These receptors are G protein-coupled receptors (GPCRs) with distinct signaling pathways: M2 and M4 primarily couple to Gi/o proteins to inhibit adenylyl cyclase and regulate ion channels, while M5 couples to Gq/11 to activate the phospholipase C pathway. M2 receptors are prominently expressed in the heart, where they regulate heart rate and conduction, and in the brain as inhibitory autoreceptors. M4 receptors are highly concentrated in the striatum and are critical for modulating dopaminergic signaling, making them key targets for neuropsychiatric conditions like schizophrenia. M5 receptors are localized on midbrain dopamine neurons and play a role in reward and addiction processes. Therapeutic agents targeting these receptors include non-selective antagonists like atropine and scopolamine, as well as newer subtype-preferring agents like xanomeline. A major challenge in drug development is achieving subtype selectivity to avoid peripheral side effects, such as M2-mediated bradycardia or M3-mediated gastrointestinal distress.

Other names

CHRM2CHRM4CHRM5Cholinergic receptor muscarinic 2Cholinergic receptor muscarinic 4Cholinergic receptor muscarinic 5M2, M4, and M5 muscarinic receptors

Agonist, Antagonist, Positive Allosteric Modulator (PAM)