Muscarinic acetylcholine receptor M4 (CHRM4) and Muscarinic acetylcholine receptor M5 (CHRM5) (M4/M5 mAChR)

The muscarinic acetylcholine receptors M4 and M5 (CHRM4 and CHRM5) are G protein-coupled receptors (GPCRs) that mediate the effects of acetylcholine in the central and peripheral nervous systems [6, 11, 22]. M4 is primarily a Gi/o-coupled receptor that acts as an inhibitory autoreceptor in the striatum, where it plays a critical role in regulating dopaminergic neurotransmission and locomotor activity [1, 4, 9]. M5 is a Gq-coupled receptor expressed in the ventral tegmental area and substantia nigra, where it modulates reward circuitry and dopamine release [15, 16, 23]. These receptors have emerged as significant therapeutic targets for neuropsychiatric and neurodegenerative disorders, particularly schizophrenia and Alzheimer's disease [1, 3, 10, 11]. M4 agonists and positive allosteric modulators (PAMs) are being developed to treat psychotic symptoms by dampening overactive dopaminergic signaling without the motor side effects of traditional D2 antagonists [1, 3, 14, 15]. M5 is being investigated as a target for substance use disorders, with M5 antagonism or negative allosteric modulation (NAM) showing potential in reducing drug-seeking behavior and addiction [10, 11, 23]. Drugs like xanomeline activate M4 to provide antipsychotic effects, while peripheral antagonists like trospium are often co-administered to mitigate systemic cholinergic side effects such as nausea and sweating [3, 7, 8, 14]. Clinical trials for M4-selective agents like emraclidine have highlighted both the potential and the challenges of targeting these specific muscarinic subtypes in complex brain disorders [1, 17].

Other names

CHRM4 and CHRM5Muscarinic receptor 4 and 5mAChR M4 and M5Cholinergic receptor muscarinic 4 and 5

M4 Agonism/Positive Allosteric Modulation: Reduces presynaptic dopamine release in the striatum and modulates glutamatergic activity to alleviate psychosis and improve cognition [1, 3, 4, 14]. M5 Antagonism/Negative Allosteric Modulation: Inhibits reward-related dopamine signaling to treat addiction and substance use disorders [11, 23]. Peripheral Muscarinic Antagonism: Blocks peripheral receptors to prevent side effects like nausea and sweating caused by central agonists [3, 7, 14].