Muscarinic acetylcholine receptor M4

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External IDs	GeneCards: [1]
Orthologs
Species	Human	Mouse
Entrez	n/a	n/a
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RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
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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.

Function

M₄ muscarinic receptors are coupled to G_i/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.

Ligands

Orthosteric agonists

• acetylcholine
• carbachol
• oxotremorine

File:VU-0152100.png

VU-0152100

Positive allosteric modulators

• LY-2033298
• 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
• Himbacine
• Mamba toxin 3
• 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)

See also

• Muscarinic acetylcholine receptor

Further reading

• Goyal RK (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, Hill-Eubanks D, Jones SV (1993). "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, Bonner TI, Gershon ES, Detera-Wadleigh S (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.
• 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, Smith DH, Ramachandran J, Capon DJ (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.
• 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. doi:10.1016/0167-4781(93)90135-z. PMID 7916637.
• Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H (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, Enderich J, Wegner M, Nitsch RM (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, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH (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, Yamada S, Ando T, Kazuko F, Kawashima K (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, 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 (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.
• Wang H, Han H, Zhang L, Shi H, Schram G, Nattel S, Wang Z (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, Webber RJ, Grando SA (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, Kahn RA, Hall RA, Levey AI (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, McKenzie J, Scarr E (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.