Muscarinic acetylcholine receptor M4 (CHRM4) (CHRM4)

The Muscarinic acetylcholine receptor M4 (CHRM4) is a G protein-coupled receptor primarily expressed in the central nervous system, with high density in the striatum, cerebral cortex, and hippocampus [2, 3, 7]. It belongs to the M2/M4 subfamily of muscarinic receptors, which typically couple to Gi/o proteins to inhibit adenylate cyclase activity and decrease intracellular cyclic AMP (cAMP) levels [1, 6, 12]. In the striatum, M4 receptors function as both inhibitory autoreceptors on cholinergic interneurons and heteroreceptors on spiny projection neurons, where they play a critical role in balancing dopaminergic and cholinergic signaling [2, 7, 11]. This regulatory function makes the M4 receptor a high-priority therapeutic target for neuropsychiatric and movement disorders, such as schizophrenia and Parkinson's disease [6, 14]. Activation of M4 receptors, either through orthosteric agonists or positive allosteric modulators (PAMs), has been shown to reduce excessive dopamine release and alleviate psychotic symptoms without the motor side effects typically associated with direct dopamine D2 receptor blockade [6, 12, 16]. Recent clinical successes, most notably the FDA approval of KarXT (a combination of the M1/M4 agonist xanomeline and the peripheral antagonist trospium), have validated the M4 receptor as a viable target for treating the positive and cognitive symptoms of schizophrenia [5, 12].

Other names

Cholinergic receptor muscarinic 4M4 receptorHM4M4RMuscarinic acetylcholine receptor 4

Activation of the receptor (via orthosteric agonism or positive allosteric modulation) triggers Gi/o protein coupling, which inhibits adenylate cyclase, reduces cAMP levels, and modulates ion channels to regulate neurotransmitter release and neuronal excitability.