Muscarinic acetylcholine receptor M4

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External IDsGeneCards: [1]
RefSeq (mRNA)



RefSeq (protein)



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The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene.[1][2]


M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[3]

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.[4][5][6] Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's Disease.[7][8][9]


Orthosteric agonists


Positive allosteric modulators


  • 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[17]
  • Himbacine
  • Mamba toxin 3[18]
  • 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)[19]

See also


  1. "Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4".
  2. Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S (May 1992). "Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4)". Genomics. 13 (1): 239–40. doi:10.1016/0888-7543(92)90236-L. PMID 1577490.
  3. Qin K, Dong C, Wu G, Lambert NA (2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nat. Chem. Biol. 7 (10): 740–7. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
  4. Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J (August 1999). "Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice". Proceedings of the National Academy of Sciences of the United States of America. 96 (18): 10483–8. doi:10.1073/pnas.96.18.10483. PMC 17915. PMID 10468635.
  5. Jeon J, Dencker D, Wörtwein G, Woldbye DP, Cui Y, Davis AA, Levey AI, Schütz G, Sager TN, Mørk A, Li C, Deng CX, Fink-Jensen A, Wess J (February 2010). "A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors". J. Neurosci. 30 (6): 2396–405. doi:10.1523/JNEUROSCI.3843-09.2010. PMC 2824442. PMID 20147565.
  6. Schmidt LS, Thomsen M, Weikop P, Dencker D, Wess J, Woldbye DP, Wortwein G, Fink-Jensen A (2011). "Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice". Psychopharmacology. 216 (3): 367–378. doi:10.1007/s00213-011-2225-4. PMC 3899540. PMID 21373792.
  7. Langmead CJ, Watson J, Reavill C (February 2008). "Muscarinic acetylcholine receptors as CNS drug targets". Pharmacology & Therapeutics. 117 (2): 232–43. doi:10.1016/j.pharmthera.2007.09.009. PMID 18082893.
  8. Stein IS, Hell JW (June 2010). "CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion". The EMBO Journal. 29 (12): 1943–5. doi:10.1038/emboj.2010.105. PMC 2892364. PMID 20551968.
  9. Guo ML, Mao LM, Wang JQ (December 2010). "Modulation of M4 muscarinic acetylcholine receptors by interacting proteins". Neuroscience Bulletin. 26 (6): 469–73. doi:10.1007/s12264-010-0933-0. PMC 3139403. PMID 21113197.
  10. Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC (2008). "Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia". PNAS. 105 (31): 10978–83. doi:10.1073/pnas.0800567105. PMC 2495016. PMID 18678919.
  11. 11.0 11.1 Brady AE, Jones CK, Bridges TM, Kennedy JP, Thompson AD, Heiman JU, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey JK, Conn PJ, Lindsley CW (2008). "Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats". J. Pharmacol. Exp. Ther. 327 (3): 941–53. doi:10.1124/jpet.108.140350. PMC 2745822. PMID 18772318.
  12. Dencker D, Weikop P, Sørensen G, et al. (2012). "An allosteric enhancer of M₄ muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine". Psychopharmacology. 224 (2): 277–87. doi:10.1007/s00213-012-2751-8. PMC 3914671. PMID 22648127.
  13. Byun NE, Grannan M, Bubser M, et al. (2014). "Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100". Neuropsychopharmacology. 39 (7): 1578–93. doi:10.1038/npp.2014.2. PMC 4023154. PMID 24442096.
  14. Galloway CR, Lebois EP, Shagarabi SL, Hernandez NA, Manns JR (2014). "Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats". Pharmacology. 93 (1–2): 57–64. doi:10.1159/000357682. PMID 24480931.
  15. Pancani T, Bolarinwa C, Smith Y, Lindsley CW, Conn PJ, Xiang Z (2014). "M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses". ACS Chem Neurosci. 5 (4): 318–24. doi:10.1021/cn500003z. PMC 3990947. PMID 24528004.
  16. Huynh T, Valant C, Crosby IT, Sexton PM, Christopoulos A, Capuano B (2013). "Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor". J. Med. Chem. 56 (20): 8196–200. doi:10.1021/jm401032k. PMID 24074052.
  17. Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK (June 2005). "Muscarinic M2 and M4 receptors in anterior cingulate cortex: relation to neuropsychiatric symptoms in dementia with Lewy bodies". Behavioural Brain Research. 161 (2): 299–305. doi:10.1016/j.bbr.2005.02.019. PMID 15922057.
  19. Lazareno S, Buckley NJ, Roberts FF (December 1990). "Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells". Molecular Pharmacology. 38 (6): 805–15. PMID 2250662.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.