Muscarinic acetylcholine receptor M4 explained

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]}

Function

M₄ muscarinic receptors are coupled to G_i/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]}

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.^{[10] [11] [12]}

Ligands

Agonists

• Acetylcholine
• Carbachol
• CMI-936^[13]
• NBI-1117568 (HTL-0016878)^[14]
• ML-007^[15]
• Oxotremorine
• Xanomeline

Positive allosteric modulators

• Emraclidine (CVL-231, PF-06852231)^[16]
• LY-2033298^{[17] [18]}
• NS-136^[19]
• SUVN-L3307032^[20]
• VU-0152100 (ML-108)^{[21] [22] [23] [24] [25] [26]}
• VU-0152099^[21]

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^[27]
• Diphenhydramine
• Himbacine
• Mamba toxin 3^[28]
• NBI-1076968^[29]
• 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)^[30]

See also

• Muscarinic acetylcholine receptor

Further reading

• Goyal RK . Muscarinic receptor subtypes. Physiology and clinical implications . N. Engl. J. Med. . 321 . 15 . 1022–9 . 1989 . 2674717 . 10.1056/NEJM198910123211506 .
• Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV . Muscarinic acetylcholine receptor subtypes: localization and structure/function . Prog. Brain Res. . 98 . 121–7 . 1993 . 8248499 . 10.1016/S0079-6123(08)62388-2 .
• Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S . Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4) . Genomics . 13 . 1 . 239–40 . 1992 . 1577490 . 10.1016/0888-7543(92)90236-L .
• Detera-Wadleigh SD, Wiesch D, Bonner TI . An SstI polymorphism for the human muscarinic acetylcholine receptor gene, m4 (CHRM 4). . Nucleic Acids Res. . 17 . 15 . 6431 . 1989 . 2570410 . 318330 . 10.1093/nar/17.15.6431 .
• Ashkenazi A, Ramachandran J, Capon DJ . Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. . Nature . 340 . 6229 . 146–50 . 1989 . 2739737 . 10.1038/340146a0 . 1989Natur.340..146A . 4312544 .
• Bonner TI, Buckley NJ, Young AC, Brann MR . Identification of a family of muscarinic acetylcholine receptor genes. . Science . 237 . 4814 . 527–32 . 1987 . 3037705 . 10.1126/science.3037705 . 1987Sci...237..527B .
• Bonner TI, Young AC, Brann MR, Buckley NJ . Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. . Neuron . 1 . 5 . 403–10 . 1990 . 3272174 . 10.1016/0896-6273(88)90190-0 . 833230 .
• Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ . Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. . EMBO J. . 6 . 13 . 3923–9 . 1988 . 3443095 . 553870 . 10.1002/j.1460-2075.1987.tb02733.x.
• van Koppen CJ, Lenz W, Nathanson NM . Isolation, sequence and functional expression of the mouse m4 muscarinic acetylcholine receptor gene. . Biochim. Biophys. Acta . 1173 . 3 . 342–4 . 1993 . 7916637 . 10.1016/0167-4781(93)90135-z .
• Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H . Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C. . J. Biol. Chem. . 271 . 5 . 2776–82 . 1996 . 8576254 . 10.1074/jbc.271.5.2776 . free .
• von der Kammer H, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch RM . Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. . J. Biol. Chem. . 273 . 23 . 14538–44 . 1998 . 9603968 . 10.1074/jbc.273.23.14538 . free .
• Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH . SH3 binding domains in the dopamine D4 receptor. . Biochemistry . 37 . 45 . 15726–36 . 1998 . 9843378 . 10.1021/bi981634+.
• Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K . Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. . Neurosci. Lett. . 266 . 1 . 17–20 . 1999 . 10336173 . 10.1016/S0304-3940(99)00259-1 . 43548155 .
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ . Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. . Proc. Natl. Acad. Sci. U.S.A. . 97 . 7 . 3491–6 . 2000 . 10737800 . 16267 . 10.1073/pnas.97.7.3491 . 2000PNAS...97.3491D . free .
• Wang H, Han H, Zhang L, Shi H, Schram G, Nattel S, Wang Z . Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart. . Mol. Pharmacol. . 59 . 5 . 1029–36 . 2001 . 11306684 . 10.1124/mol.59.5.1029.
• Buchli R, Ndoye A, Arredondo J, Webber RJ, Grando SA . Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes. . Mol. Cell. Biochem. . 228 . 1–2 . 57–72 . 2002 . 11855742 . 10.1023/A:1013368509855 . 10788646 .
• McClatchy DB, Knudsen CR, Clark BF, Kahn RA, Hall RA, Levey AI . Novel interaction between the M4 muscarinic acetylcholine receptor and elongation factor 1A2 . J. Biol. Chem. . 277 . 32 . 29268–74 . 2002 . 12048193 . 10.1074/jbc.M203081200 . free .
• Dean B, McLeod M, Keriakous D, McKenzie J, Scarr E . Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia . Mol. Psychiatry . 7 . 10 . 1083–91 . 2003 . 12476323 . 10.1038/sj.mp.4001199 . free .

Notes and References

1. Web site: Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4.
2. Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S . Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4) . Genomics . 13 . 1 . 239–40 . May 1992 . 1577490 . 10.1016/0888-7543(92)90236-L .
3. Qin K, Dong C, Wu G, Lambert NA . Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers . Nat. Chem. Biol. . 7 . 10 . 740–7 . 2011 . 21873996 . 3177959 . 10.1038/nchembio.642 .
4. Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J . 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 . August 1999 . 10468635 . 17915 . 10.1073/pnas.96.18.10483 . 1999PNAS...9610483G . free .
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 . A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors . J. Neurosci. . 30 . 6 . 2396–405 . February 2010 . 20147565 . 2824442 . 10.1523/JNEUROSCI.3843-09.2010 .
6. Schmidt LS, Thomsen M, Weikop P, Dencker D, Wess J, Woldbye DP, Wortwein G, Fink-Jensen A . Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice . Psychopharmacology . 216 . 3 . 367–378 . 2011 . 21373792 . 3899540. 10.1007/s00213-011-2225-4 .
7. Langmead CJ, Watson J, Reavill C . Muscarinic acetylcholine receptors as CNS drug targets . Pharmacology & Therapeutics . 117 . 2 . 232–43 . February 2008 . 18082893 . 10.1016/j.pharmthera.2007.09.009 .
8. Stein IS, Hell JW . CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion . The EMBO Journal . 29 . 12 . 1943–5 . June 2010 . 20551968 . 2892364 . 10.1038/emboj.2010.105 .
9. Guo ML, Mao LM, Wang JQ . Modulation of M4 muscarinic acetylcholine receptors by interacting proteins . Neuroscience Bulletin . 26 . 6 . 469–73 . December 2010 . 21113197 . 3139403 . 10.1007/s12264-010-0933-0 .
10. Trivedi G, Inoue D, Chen C, Bitner L, Chung YR, Taylor J, Gönen M, Wess J, Abdel-Wahab O, Zhang L . Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors . Science Translational Medicine . 11 . 511 . eaaw3781 . September 2019 . 31554738 . 10.1126/scitranslmed.aaw3781 . 7194030 .
11. Baeten J, Liu W, Preddy I, Zhou N, McNerney M . CRISPR screening in human hematopoietic stem and progenitor cells reveals an enrichment for tumor suppressor genes within chromosome 7 commonly deleted regions . Leukemia . 36 . 5 . 1421-1425 . Jan 2022 . 35034954 . 10.1038/s41375-021-01491-z . 9064908 .
12. Trivedi G, Inoue D, Zhang L . Targeting low-risk myelodysplastic syndrome with novel therapeutic strategies . Trends in Molecular Medicine . 27 . 10 . 990-999 . Oct 2021 . 34257007 . 10.1016/j.molmed.2021.06.013 . 8487963 .
13. Web site: CMI 936 . AdisInsight . 29 August 2002 . 21 October 2024.
14. Web site: HTL 0016878 . AdisInsight . 2 September 2024 . 21 October 2024.
15. Web site: ML 007 . AdisInsight . 9 January 2024 . 21 October 2024.
16. Web site: Cerevel Therapeutics . AdisInsight . 28 August 2024 . 21 October 2024.
17. Web site: Research programme: muscarinic acetylcholine M4 receptor allosteric modulators (LY-2033298) . AdisInsight . 16 July 2016 . 21 October 2024.
18. Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC . Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia . PNAS . 105 . 31 . 10978–83 . 2008 . 18678919 . 2495016 . 10.1073/pnas.0800567105 . 2008PNAS..10510978C . free .
19. Web site: NS 136 . AdisInsight . 15 May 2024 . 21 October 2024.
20. Web site: SUVN L3307032 . AdisInsight . 10 October 2024 . 21 October 2024.
21. 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 . 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 . 2008 . 18772318 . 2745822 . 10.1124/jpet.108.140350 .
22. Dencker D, Weikop P, Sørensen G, etal . An allosteric enhancer of M₄ muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine . Psychopharmacology . 224 . 2 . 277–87 . 2012 . 22648127 . 3914671 . 10.1007/s00213-012-2751-8 .
23. Byun NE, Grannan M, Bubser M, etal . Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100 . Neuropsychopharmacology . 39 . 7 . 1578–93 . 2014 . 24442096 . 10.1038/npp.2014.2 . 4023154.
24. Galloway CR, Lebois EP, Shagarabi SL, Hernandez NA, Manns JR . Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats . Pharmacology . 93 . 1–2 . 57–64 . 2014 . 24480931 . 10.1159/000357682 . 10402346 .
25. Pancani T, Bolarinwa C, Smith Y, Lindsley CW, Conn PJ, Xiang Z . M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses . ACS Chem Neurosci . 5 . 4 . 318–24 . 2014 . 24528004 . 10.1021/cn500003z . 3990947.
26. Huynh T, Valant C, Crosby IT, Sexton PM, Christopoulos A, Capuano B . Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor . J. Med. Chem. . 56 . 20 . 8196–200 . 2013 . 24074052 . 10.1021/jm401032k .
27. Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK . 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 . June 2005 . 15922057 . 10.1016/j.bbr.2005.02.019 . 34247659 .
28. Web site: Muscarinic toxin 3 - Dendroaspis angusticeps (Eastern green mamba) .
29. Web site: NBI 1076968 . AdisInsight . Springer Nature Switzerland AG . 11 September 2024 . 20 October 2024.
30. Lazareno S, Buckley NJ, Roberts FF . Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells . Molecular Pharmacology . 38 . 6 . 805–15 . December 1990 . 2250662 .