Muscarinic acetylcholine receptor M4

{{Short description|Protein-coding gene}} {{DISPLAYTITLE:Muscarinic acetylcholine receptor M4}} {{Infobox_gene}}  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.<ref name="entrez">{{cite web | title = Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1132}}</ref><ref name="pmid1577490">{{cite journal |vauthors=Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S | title = Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4) | journal = Genomics | volume = 13 | issue = 1 | pages = 239–40 | date = May 1992 | pmid = 1577490 | doi = 10.1016/0888-7543(92)90236-L | url = https://zenodo.org/record/1258587}}</ref>

==Function== M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.<ref name="Kou Qin">{{cite journal |vauthors=Qin K, Dong C, Wu G, Lambert NA | title = Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers | journal = Nat. Chem. Biol. | volume = 7 | issue = 10 | pages = 740–7 | year = 2011 | pmid = 21873996 | pmc = 3177959 | doi = 10.1038/nchembio.642 }}</ref>

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.<ref name="pmid10468635">{{cite journal |vauthors=Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J | title = Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 18 | pages = 10483–8 | date = August 1999 | pmid = 10468635 | pmc = 17915 | doi = 10.1073/pnas.96.18.10483 | bibcode = 1999PNAS...9610483G | doi-access = free }}</ref><ref name="pmid20147565">{{cite journal |vauthors=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 | title = A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors | journal = J. Neurosci. | volume = 30 | issue = 6 | pages = 2396–405 | date = February 2010 | pmid = 20147565 | pmc = 2824442 | doi = 10.1523/JNEUROSCI.3843-09.2010 }}</ref><ref>{{cite journal |vauthors=Schmidt LS, Thomsen M, Weikop P, Dencker D, Wess J, Woldbye DP, Wortwein G, Fink-Jensen A | title = Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice | journal = Psychopharmacology | volume = 216 | issue = 3 | pages = 367–378 | year = 2011 | pmid = 21373792 | pmc = 3899540| doi = 10.1007/s00213-011-2225-4 }}</ref> Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's disease.<ref name="pmid18082893">{{cite journal |vauthors=Langmead CJ, Watson J, Reavill C | title = Muscarinic acetylcholine receptors as CNS drug targets | journal = Pharmacology & Therapeutics | volume = 117 | issue = 2 | pages = 232–43 | date = February 2008 | pmid = 18082893 | doi = 10.1016/j.pharmthera.2007.09.009 }}</ref><ref name="pmid20551968">{{cite journal |vauthors=Stein IS, Hell JW | title = CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion | journal = The EMBO Journal | volume = 29 | issue = 12 | pages = 1943–5 | date = June 2010 | pmid = 20551968 | pmc = 2892364 | doi = 10.1038/emboj.2010.105 }}</ref><ref name="pmid21113197">{{cite journal |vauthors=Guo ML, Mao LM, Wang JQ | title = Modulation of M4 muscarinic acetylcholine receptors by interacting proteins | journal = Neuroscience Bulletin | volume = 26 | issue = 6 | pages = 469–73 | date = December 2010 | pmid = 21113197 | pmc = 3139403 | doi = 10.1007/s12264-010-0933-0 }}</ref>

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.<ref name="pmid31554738">{{cite journal |vauthors=Trivedi G, Inoue D, Chen C, Bitner L, Chung YR, Taylor J, Gönen M, Wess J, Abdel-Wahab O, Zhang L | title = Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors | journal = Science Translational Medicine | volume = 11 | issue = 511 | article-number = eaaw3781 | date = September 2019 | pmid = 31554738 | doi = 10.1126/scitranslmed.aaw3781 | pmc = 7194030 }}</ref><ref name="pmid35034954">{{cite journal |vauthors= Baeten J, Liu W, Preddy I, Zhou N, McNerney M | title = CRISPR screening in human hematopoietic stem and progenitor cells reveals an enrichment for tumor suppressor genes within chromosome 7 commonly deleted regions | journal = Leukemia | volume = 36 | issue = 5 | pages = 1421-1425 | date = Jan 2022 | pmid = 35034954 | doi = 10.1038/s41375-021-01491-z | pmc = 9064908 }}</ref><ref name="pmid34257007">{{cite journal |vauthors=Trivedi G, Inoue D, Zhang L | title = Targeting low-risk myelodysplastic syndrome with novel therapeutic strategies | journal = Trends in Molecular Medicine | volume = 27 | issue = 10 | pages = 990-999 | date = Oct 2021 | pmid = 34257007 | doi = 10.1016/j.molmed.2021.06.013 | pmc = 8487963 }}</ref><ref name="pmid35084368">{{cite journal |vauthors= Jotte M, McNerney M | title = The significance of CUX1 and chromosome 7 in myeloid malignancies | journal = Current Opinion in Hematology | volume = 29 | issue = 2 | pages = 92-102 | date = Mar 2022 | pmid = 35084368 | doi = 10.1097/MOH.0000000000000699 | pmc = 8795693 }}</ref>

==Ligands==

===Agonists=== * Acetylcholine * Carbachol * CMI-936<ref name="AdisInsight-CMI-936">{{cite web | title=CMI 936 | website=AdisInsight | date=29 August 2002 | url=https://adisinsight.springer.com/drugs/800011771 | access-date=21 October 2024}}</ref> * NBI-1117568 (HTL-0016878)<ref name="AdisInsight-HTL-0016878">{{cite web | title=HTL 0016878 | website=AdisInsight | date=2 September 2024 | url=https://adisinsight.springer.com/drugs/800050085 | access-date=21 October 2024}}</ref> * ML-007<ref name="AdisInsight-ML-007">{{cite web | title=ML 007 | website=AdisInsight | date=9 January 2024 | url=https://adisinsight.springer.com/drugs/800062983 | access-date=21 October 2024}}</ref> * Oxotremorine * Xanomeline

===Positive allosteric modulators=== * Emraclidine (CVL-231, PF-06852231)<ref name="AdisInsight-Emraclidine">{{cite web | title=Cerevel Therapeutics | website=AdisInsight | date=28 August 2024 | url=https://adisinsight.springer.com/drugs/800056372 | access-date=21 October 2024}}</ref> * LY-2033298<ref name="AdisInsight">{{cite web | title=Research programme: muscarinic acetylcholine M4 receptor allosteric modulators (LY-2033298) | website=AdisInsight | date=16 July 2016 | url=https://adisinsight.springer.com/drugs/800030204 | access-date=21 October 2024}}</ref><ref name="pmid18678919">{{cite journal |vauthors=Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC | title = Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia | journal = PNAS | volume = 105 | issue = 31 | pages = 10978–83 | year = 2008 | pmid = 18678919 | pmc = 2495016 | doi = 10.1073/pnas.0800567105 | bibcode = 2008PNAS..10510978C | doi-access = free }}</ref> * NS-136<ref name="AdisInsight-NS-136">{{cite web | title=NS 136 | website=AdisInsight | date=15 May 2024 | url=https://adisinsight.springer.com/drugs/800075213 | access-date=21 October 2024}}</ref> * SUVN-L3307032<ref name="AdisInsight-SUVN-L3307032">{{cite web | title=SUVN L3307032 | website=AdisInsight | date=10 October 2024 | url=https://adisinsight.springer.com/drugs/800079834 | access-date=21 October 2024}}</ref> * VU-0152100 (ML-108)<ref name="pmid18772318">{{cite journal |vauthors=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 | title = Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats | journal = J. Pharmacol. Exp. Ther. | volume = 327 | issue = 3 | pages = 941–53 | year = 2008 | pmid = 18772318 | pmc = 2745822 | doi = 10.1124/jpet.108.140350 }}</ref><ref name="pmid22648127">{{cite journal |vauthors=Dencker D, Weikop P, Sørensen G, etal |title=An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine |journal=Psychopharmacology |volume=224 |issue=2 |pages=277–87 |year=2012 |pmid=22648127 |pmc=3914671 |doi=10.1007/s00213-012-2751-8 }}</ref><ref name="pmid24442096">{{cite journal |vauthors=Byun NE, Grannan M, Bubser M, etal |title=Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100 |journal=Neuropsychopharmacology |volume=39 |issue=7 |pages=1578–93 |year=2014 |pmid=24442096 |doi=10.1038/npp.2014.2 |pmc=4023154}}</ref><ref name="pmid24480931">{{cite journal |vauthors=Galloway CR, Lebois EP, Shagarabi SL, Hernandez NA, Manns JR |title=Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats |journal=Pharmacology |volume=93 |issue=1–2 |pages=57–64 |year=2014 |pmid=24480931 |doi=10.1159/000357682 |s2cid=10402346 }}</ref><ref name="pmid24528004">{{cite journal |vauthors=Pancani T, Bolarinwa C, Smith Y, Lindsley CW, Conn PJ, Xiang Z |title=M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses |journal=ACS Chem Neurosci |volume=5 |issue=4 |pages=318–24 |year=2014 |pmid=24528004 |doi=10.1021/cn500003z |pmc=3990947}}</ref><ref name="pmid24074052">{{cite journal |vauthors=Huynh T, Valant C, Crosby IT, Sexton PM, Christopoulos A, Capuano B |title=Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor |journal=J. Med. Chem. |volume=56 |issue=20 |pages=8196–200 |year=2013 |pmid=24074052 |doi=10.1021/jm401032k }}</ref> * VU-0152099<ref name="pmid18772318"/>

===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<ref name="pmid15922057">{{cite journal |vauthors=Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK | title = Muscarinic M2 and M4 receptors in anterior cingulate cortex: relation to neuropsychiatric symptoms in dementia with Lewy bodies | journal = Behavioural Brain Research | volume = 161 | issue = 2 | pages = 299–305 | date = June 2005 | pmid = 15922057 | doi = 10.1016/j.bbr.2005.02.019 | s2cid = 34247659 }}</ref> * Diphenhydramine * Himbacine * Mamba toxin 3<ref>{{cite web | url=https://www.uniprot.org/uniprot/P81031 | title=Muscarinic toxin 3 - Dendroaspis angusticeps (Eastern green mamba) }}</ref> * NBI-1076968<ref name="AdisInsight-NBI-1076968">{{cite web | title=NBI 1076968 | work = AdisInsight | publisher = Springer Nature Switzerland AG | date=11 September 2024 | url=https://adisinsight.springer.com/drugs/800079297 | access-date=20 October 2024}}</ref> * 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)<ref name="pmid2250662">{{cite journal |vauthors=Lazareno S, Buckley NJ, Roberts FF | title = Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells | journal = Molecular Pharmacology | volume = 38 | issue = 6 | pages = 805–15 | date = December 1990 | pmid = 2250662 }}</ref> * VU6028418

==See also== * Muscarinic acetylcholine receptor

==References== {{reflist|35em}}

==Further reading== {{refbegin|35em}} * {{cite journal | author = Goyal RK | title = Muscarinic receptor subtypes. Physiology and clinical implications | journal = N. Engl. J. Med. | volume = 321 | issue = 15 | pages = 1022–9 | year = 1989 | pmid = 2674717 | doi = 10.1056/NEJM198910123211506 }} * {{cite journal |vauthors=Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV | title = Muscarinic acetylcholine receptor subtypes: localization and structure/function | journal = Prog. Brain Res. | volume = 98 | pages = 121–7 | year = 1993 | pmid = 8248499 | doi = 10.1016/S0079-6123(08)62388-2 }} * {{cite journal |vauthors=Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S | title = Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4) | journal = Genomics | volume = 13 | issue = 1 | pages = 239–40 | year = 1992 | pmid = 1577490 | doi = 10.1016/0888-7543(92)90236-L | url = https://zenodo.org/record/1258587 }} * {{cite journal |vauthors=Detera-Wadleigh SD, Wiesch D, Bonner TI | title = An SstI polymorphism for the human muscarinic acetylcholine receptor gene, m4 (CHRM 4). | journal = Nucleic Acids Res. | volume = 17 | issue = 15 | page = 6431 | year = 1989 | pmid = 2570410 | pmc = 318330 | doi = 10.1093/nar/17.15.6431 }} * {{cite journal |vauthors=Ashkenazi A, Ramachandran J, Capon DJ | title = Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. | journal = Nature | volume = 340 | issue = 6229 | pages = 146–50 | year = 1989 | pmid = 2739737 | doi = 10.1038/340146a0 | bibcode = 1989Natur.340..146A | s2cid = 4312544 }} * {{cite journal |vauthors=Bonner TI, Buckley NJ, Young AC, Brann MR | title = Identification of a family of muscarinic acetylcholine receptor genes. | journal = Science | volume = 237 | issue = 4814 | pages = 527–32 | year = 1987 | pmid = 3037705 | doi = 10.1126/science.3037705 | bibcode = 1987Sci...237..527B | url = https://zenodo.org/record/1231199 }} * {{cite journal |vauthors=Bonner TI, Young AC, Brann MR, Buckley NJ | title = Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. | journal = Neuron | volume = 1 | issue = 5 | pages = 403–10 | year = 1990 | pmid = 3272174 | doi = 10.1016/0896-6273(88)90190-0 | s2cid = 833230 }} * {{cite journal |vauthors=Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ | title = Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. | journal = EMBO J. | volume = 6 | issue = 13 | pages = 3923–9 | year = 1988 | pmid = 3443095 | pmc = 553870 | doi = 10.1002/j.1460-2075.1987.tb02733.x}} * {{cite journal |vauthors=van Koppen CJ, Lenz W, Nathanson NM | title = Isolation, sequence and functional expression of the mouse m4 muscarinic acetylcholine receptor gene. | journal = Biochim. Biophys. Acta | volume = 1173 | issue = 3 | pages = 342–4 | year = 1993 | pmid = 7916637 | doi = 10.1016/0167-4781(93)90135-z }} * {{cite journal |vauthors=Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H | title = Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C. | journal = J. Biol. Chem. | volume = 271 | issue = 5 | pages = 2776–82 | year = 1996 | pmid = 8576254 | doi = 10.1074/jbc.271.5.2776 | doi-access = free }} * {{cite journal |vauthors=von der Kammer H, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch RM | title = Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. | journal = J. Biol. Chem. | volume = 273 | issue = 23 | pages = 14538–44 | year = 1998 | pmid = 9603968 | doi = 10.1074/jbc.273.23.14538 | doi-access = free }} * {{cite journal |vauthors=Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH | title = SH3 binding domains in the dopamine D4 receptor. | journal = Biochemistry | volume = 37 | issue = 45 | pages = 15726–36 | year = 1998 | pmid = 9843378 | doi = 10.1021/bi981634+| url = http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0017/NQ45764.pdf }} * {{cite journal |vauthors=Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K | title = Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. | journal = Neurosci. Lett. | volume = 266 | issue = 1 | pages = 17–20 | year = 1999 | pmid = 10336173 | doi = 10.1016/S0304-3940(99)00259-1 | s2cid = 43548155 }} * {{cite journal |vauthors=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 | title = Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 7 | pages = 3491–6 | year = 2000 | pmid = 10737800 | pmc = 16267 | doi = 10.1073/pnas.97.7.3491 | bibcode = 2000PNAS...97.3491D | doi-access = free }} * {{cite journal |vauthors=Wang H, Han H, Zhang L, Shi H, Schram G, Nattel S, Wang Z | title = Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart. | journal = Mol. Pharmacol. | volume = 59 | issue = 5 | pages = 1029–36 | year = 2001 | pmid = 11306684 | doi = 10.1124/mol.59.5.1029}} * {{cite journal |vauthors=Buchli R, Ndoye A, Arredondo J, Webber RJ, Grando SA | title = Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes. | journal = Mol. Cell. Biochem. | volume = 228 | issue = 1–2 | pages = 57–72 | year = 2002 | pmid = 11855742 | doi = 10.1023/A:1013368509855 | s2cid = 10788646 }} * {{cite journal |vauthors=McClatchy DB, Knudsen CR, Clark BF, Kahn RA, Hall RA, Levey AI | title = Novel interaction between the M4 muscarinic acetylcholine receptor and elongation factor 1A2 | journal = J. Biol. Chem. | volume = 277 | issue = 32 | pages = 29268–74 | year = 2002 | pmid = 12048193 | doi = 10.1074/jbc.M203081200 | doi-access = free }} * {{cite journal |vauthors=Dean B, McLeod M, Keriakous D, McKenzie J, Scarr E | title = Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia | journal = Mol. Psychiatry | volume = 7 | issue = 10 | pages = 1083–91 | year = 2003 | pmid = 12476323 | doi = 10.1038/sj.mp.4001199 | doi-access = free }} {{refend}}

== External links == * {{PDBe-KB2|P08173|Muscarinic acetylcholine receptor M4}}

{{DEFAULTSORT:Muscarinic Acetylcholine Receptor M4}} Category:G protein-coupled receptors Category:Human proteins Category:Muscarinic acetylcholine receptors