Muscarinic acetylcholine receptors M1 and M4 (M1 and M4 receptors (muscarinic acetylcholine receptors M1 and M4))

Muscarinic acetylcholine receptor M1 and M4 are members of the G protein-coupled receptor superfamily, activated by the neurotransmitter acetylcholine. M1 is mainly coupled to Gq proteins and is highly expressed in the cortex and hippocampus, where it is crucial for learning, memory, and cognitive processing. M4 is coupled to Gi proteins and predominates in the striatum, with an important role in regulating dopamine release, and impacting psychosis and cognitive functions. Both receptor subtypes are validated drug targets for neurodegenerative and neuropsychiatric diseases—particularly Alzheimer’s disease and schizophrenia—due to their functional importance in cognition and neuronal modulation. Clinical development of M1/M4-selective agonists and positive allosteric modulators is active, with safety profiles challenged by off-target activation of other muscarinic subtypes.

Other names

M1 muscarinic receptorM4 muscarinic receptormAChR M1mAChR M4Muscarinic receptor M1Muscarinic receptor M4

Drugs targeting M1 and M4 receptors can act via orthosteric agonism, activating the receptor at the acetylcholine-binding site. They can also achieve allosteric agonism or modulation by binding to non-canonical receptor sites to potentiate activity or selectivity. Inverse agonism, which blocks basal receptor activity, is another mechanism. For M4, there's also an indirect dopamine modulation.