Muscarinic acetylcholine receptor M4

Function

M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.

They function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.

Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission. Activation of M4 receptors in the striatum inhibit D1-induced locomotor stimulation in mice. M4 receptor-deficient mice exhibit increased locomotor simulation in response to D1 agonists, amphetamine and cocaine. Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's disease.

The M4 muscarinic receptor has been found to be a regulator of erythroid progenitor cell differentiation. Inhibition of the M4 muscarinic receptor provides therapeutic benefits in myelodysplastic syndrome and anemia.

Ligands

Agonists

• Acetylcholine
• Carbachol
• CMI-936
• NBI-1117568 (HTL-0016878)
• ML-007
• Oxotremorine
• Xanomeline

Positive allosteric modulators

• Emraclidine (CVL-231, PF-06852231)
• LY-2033298
• NS-136
• SUVN-L3307032
• VU-0152100 (ML-108)
• VU-0152099

Antagonists

• AFDX-384 (mixed M2/M4 antagonist, N-[2-[2-[(Dipropylamino)methyl]-1-piperidinyl]ethyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide, CAS# 118290-27-0)
• Dicycloverine
• Diphenhydramine
• Himbacine
• Mamba toxin 3
• NBI-1076968
• PD-102,807 (3,6a,11,14-Tetrahydro-9-methoxy-2-methyl-(12H)-isoquino[1,2-b]pyrrolo[3,2-f][1,3]benzoxazine-1-carboxylic acid ethyl ester, CAS# 23062-91-1)
• PD-0298029
• Tropicamide - moderate selectivity over other muscarinic subtypes (2-5x approx)
• VU6028418

References

References

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10. (September 2019). "Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors". Science Translational Medicine.
11. (Jan 2022). "CRISPR screening in human hematopoietic stem and progenitor cells reveals an enrichment for tumor suppressor genes within chromosome 7 commonly deleted regions". Leukemia.
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21. (10 October 2024). "SUVN L3307032".
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