Muscarinic acetylcholine receptor M1, Muscarinic acetylcholine receptor M4, Muscarinic acetylcholine receptor M5 (M1, M4, M5)

Muscarinic acetylcholine receptors M1, M4, and M5 are G protein-coupled receptors (GPCRs) that mediate the effects of the neurotransmitter acetylcholine in the central and peripheral nervous systems. These subtypes are particularly prominent in the brain, where they regulate critical processes such as learning, memory, motor control, and reward. M1 and M5 receptors are coupled to Gq proteins, which activate the phospholipase C pathway, while M4 receptors are coupled to Gi proteins, which inhibit adenylyl cyclase. In the context of disease, M1 and M4 receptors are key therapeutic targets for schizophrenia and Alzheimer's disease; their activation can alleviate cognitive deficits and psychotic symptoms by modulating dopamine and glutamate circuits. M5 receptors are uniquely expressed on midbrain dopamine neurons and are being investigated for their role in substance use disorders and addiction. Drugs targeting these receptors include orthosteric agonists like xanomeline and positive allosteric modulators like emraclidine, which aim to provide efficacy with improved selectivity. A major challenge in developing muscarinic therapies has been managing peripheral cholinergic side effects, a hurdle recently overcome by combining CNS-active agonists with peripheral antagonists like trospium.

Other names

CHRM1CHRM4CHRM5M1RM4RM5RMuscarinic receptor 1Muscarinic receptor 4Muscarinic receptor 5

Agonism and positive allosteric modulation of central M1 and M4 receptors to enhance cholinergic signaling and modulate dopamine/glutamate circuits, often combined with peripheral muscarinic antagonism to reduce systemic side effects.