Muscarinic acetylcholine receptor M3 and Muscarinic acetylcholine receptor M4 (M3 receptor (CHRM3), M4 receptor (CHRM4))

Muscarinic acetylcholine receptors M3 and M4 are members of the G protein-coupled receptor (GPCR) superfamily that mediate the actions of acetylcholine in both the central and peripheral nervous systems. The M3 receptor is mainly associated with smooth muscle contraction, glandular secretion, and endothelial vasodilation, operating through Gq-mediated signaling and increases in intracellular calcium. The M4 receptor is prominent in the central nervous system (especially striatum, cortex, and hippocampus) where, through Gi coupling, it modulates neurotransmitter release (notably dopamine), exerts inhibitory effects, and is implicated in cognitive, neuropsychiatric, and potentially analgesic functions. Both receptors are considered important therapeutic targets in a range of diseases, including COPD, bladder disorders, schizophrenia, certain cancers, pain syndromes, and neurodegenerative diseases. Selective modulation has been a pharmacological goal to minimize side effects commonly seen with non-selective muscarinic ligands.

Other names

Muscarinic acetylcholine receptor M3CHRM3Muscarinic acetylcholine receptor M4CHRM4mAChR M3mAChR M4Muscarinic receptor subtype M3Muscarinic receptor subtype M4

Antagonists block receptor-mediated acetylcholine responses, inhibiting bronchoconstriction (M3), gland secretion (M3), or other parasympathetic effects. Agonists stimulate the respective signaling pathways: M3 typically increases intracellular calcium (Gq), causing smooth muscle contraction or gland secretion; M4 reduces cAMP via Gi, typically yielding inhibitory effects, including modulation of neurotransmitter release. Positive allosteric modulators enhance the receptor response to acetylcholine without directly activating it (notably M4 in schizophrenia). CNS-active agonists or modulators can adjust dopamine levels (M4), relevant for schizophrenia and Parkinson's.