Muscarinic acetylcholine receptor M4 and M5 (mAChR M4/M5)

Muscarinic acetylcholine receptors M4 and M5 (mAChR M4 and M5) are G protein-coupled receptors (GPCRs) that play distinct yet complementary roles in the central nervous system [1, 2]. The M4 receptor is primarily coupled to Gi/o proteins and is highly expressed in the striatum, where it functions as an inhibitory regulator of dopamine release, making it a significant target for antipsychotic and pro-cognitive therapies in schizophrenia and Alzheimer's disease [3, 6, 10]. The M5 receptor is coupled to Gq/11 proteins and is localized in the midbrain dopaminergic neurons, where it modulates reward-seeking behavior and cerebral blood vessel dilation [11, 13]. Drugs targeting these receptors, such as xanomeline (an M1/M4 agonist) and various subtype-selective allosteric modulators, aim to treat psychiatric disorders, addiction, and neurodegenerative conditions [4, 15, 20]. Selective modulation of M4 and M5 is a major area of research to avoid the adverse peripheral cholinergic effects, such as gastrointestinal distress and salivation, typically seen with non-selective muscarinic agonists [10, 16].

Other names

CHRM4CHRM5Muscarinic 4Muscarinic 5mAChR4mAChR5Cholinergic receptor muscarinic 4Cholinergic receptor muscarinic 5

M4 receptors are Gi/o-coupled and inhibit adenylyl cyclase, while M5 receptors are Gq/11-coupled and activate phospholipase C [1, 4, 8]. Drugs targeting these receptors act as agonists, positive allosteric modulators (PAMs), or negative allosteric modulators (NAMs) to modulate neurotransmission, particularly dopamine signaling [6, 10, 11].