Muscarinic acetylcholine receptor M4

Cholinergic receptor, muscarinic 4
Identifiers
Symbols	CHRM4; HM4; M4R
External IDs	OMIM: 118495 MGI: 88399 HomoloGene: 20192 GeneCards: CHRM4 Gene
Gene Ontology Molecular function • receptor activity • G-protein coupled receptor activity • muscarinic acetylcholine receptor activity • guanyl-nucleotide exchange factor activity Cellular component • membrane fraction • plasma membrane • plasma membrane • integral to plasma membrane • postsynaptic density • cell junction • asymmetric synapse • sarcolemma • neuronal cell body • axon terminus • intracellular part • postsynaptic membrane Biological process • signal transduction • cell surface receptor linked signaling pathway • inhibition of adenylate cyclase activity by muscarinic acetylcholine receptor signaling pathway • muscarinic acetylcholine receptor signaling pathway • cell proliferation • response to organic substance Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1132	12672
Ensembl	ENSG00000180720	ENSMUSG00000040495
UniProt	P08173	Q0VBU3
RefSeq (mRNA)	NM_000741	NM_007699.2
RefSeq (protein)	NP_000732	NP_031725.1
Location (UCSC)	Chr 11: 46.41 – 46.41 Mb	Chr 2: 91.76 – 91.77 Mb
PubMed search	[1]	[2]

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

The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel modulation. Muscarinic receptors mediate many effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor are unknown; however, mouse studies link its function to adenylyl cyclase inhibition.^[1]

M₄ muscarinic receptors 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.^[3][4][5] Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M₄ activity may contribute to conditions such as Parkinson's Disease.^[6][7][8]

Ligands

Orthosteric agonists

• acetylcholine
• carbachol
• oxotremorine

Allosteric Agonists

• LY-2033298 ^[9]
• VU-0152100
• VU-0152099 ^[10]

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^[11]
• Himbacine
• Mamba toxin 3^[12]
• 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)^[13]

See also

• Muscarinic acetylcholine receptor

References

1. ^ ^{a b} "Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1132. 
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. ^ 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. PMC 17915. PMID 10468635. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=17915. 
4. ^ Jeon J, Dencker D, Wörtwein G, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2824442. 
5. ^ Schmidt, L. S.; Thomsen, M.; Weikop, P.; Dencker, D.; Wess, J. R.; Woldbye, D. P. D.; 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. PMID 21373792.  edit
6. ^ 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. 
7. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2892364. 
8. ^ Guo ML, Mao LM, Wang JQ (December 2010). "Modulation of M4 muscarinic acetylcholine receptors by interacting proteins". Neuroscience Bulletin 26 (6): 469–73. PMC 3139403. PMID 21113197. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3139403. 
9. ^ Chan WY, McKinzie DL, Bose S, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2495016. 
10. ^ Brady AE, Jones CK, Bridges TM, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2745822. 
11. ^ 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. 
12. ^ http://www.uniprot.org/uniprot/P81031
13. ^ 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

• Goyal RK; Underhill, Lisa H.; Goyal, Raj K. (1989). "Muscarinic receptor subtypes. Physiology and clinical implications.". N. Engl. J. Med. 321 (15): 1022–9. doi:10.1056/NEJM198910123211506. PMID 2674717. 
• Brann MR, Ellis J, Jørgensen H, et al. (1994). "Muscarinic acetylcholine receptor subtypes: localization and structure/function.". Prog. Brain Res. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. PMID 8248499. 
• Grewal RP, Martinez M, Hoehe M, et al. (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. 
• Detera-Wadleigh SD, Wiesch D, Bonner TI (1989). "An SstI polymorphism for the human muscarinic acetylcholine receptor gene, m4 (CHRM 4).". Nucleic Acids Res. 17 (15): 6431. doi:10.1093/nar/17.15.6431. PMC 318330. PMID 2570410. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=318330. 
• Ashkenazi A, Ramachandran J, Capon DJ (1989). "Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes.". Nature 340 (6229): 146–50. doi:10.1038/340146a0. PMID 2739737. 
• Bonner TI, Buckley NJ, Young AC, Brann MR (1987). "Identification of a family of muscarinic acetylcholine receptor genes.". Science 237 (4814): 527–32. doi:10.1126/science.3037705. PMID 3037705. 
• Bonner TI, Young AC, Brann MR, Buckley NJ (1990). "Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes.". Neuron 1 (5): 403–10. doi:10.1016/0896-6273(88)90190-0. PMID 3272174. 
• Peralta EG, Ashkenazi A, Winslow JW, et al. (1988). "Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors.". EMBO J. 6 (13): 3923–9. PMC 553870. PMID 3443095. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=553870. 
• van Koppen CJ, Lenz W, Nathanson NM (1993). "Isolation, sequence and functional expression of the mouse m4 muscarinic acetylcholine receptor gene.". Biochim. Biophys. Acta 1173 (3): 342–4. PMID 7916637. 
• Haga K, Kameyama K, Haga T, et al. (1996). "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. doi:10.1074/jbc.271.5.2776. PMID 8576254. 
• von der Kammer H, Mayhaus M, Albrecht C, et al. (1998). "Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors.". J. Biol. Chem. 273 (23): 14538–44. doi:10.1074/jbc.273.23.14538. PMID 9603968. 
• Oldenhof J, Vickery R, Anafi M, et al. (1998). "SH3 binding domains in the dopamine D4 receptor.". Biochemistry 37 (45): 15726–36. doi:10.1021/bi981634. PMID 9843378. 
• Sato KZ, Fujii T, Watanabe Y, et al. (1999). "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. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173. 
• Dias Neto E, Correa RG, Verjovski-Almeida S, et al. (2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.". Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3491–6. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=16267. 
• Wang H, Han H, Zhang L, et al. (2001). "Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart.". Mol. Pharmacol. 59 (5): 1029–36. PMID 11306684. 
• Buchli R, Ndoye A, Arredondo J, et al. (2002). "Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes.". Mol. Cell. Biochem. 228 (1–2): 57–72. doi:10.1023/A:1013368509855. PMID 11855742. 
• McClatchy DB, Knudsen CR, Clark BF, et al. (2002). "Novel interaction between the M4 muscarinic acetylcholine receptor and elongation factor 1A2". J. Biol. Chem. 277 (32): 29268–74. doi:10.1074/jbc.M203081200. PMID 12048193. 
• Dean B, McLeod M, Keriakous D, et al. (2003). "Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia". Mol. Psychiatry 7 (10): 1083–91. doi:10.1038/sj.mp.4001199. PMID 12476323. 

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

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