Muscarinic acetylcholine receptor M₅

CHRM5
Identifiers
Aliases	CHRM5, HM5, cholinergic receptor muscarinic 5
External IDs	OMIM: 118496; MGI: 109248; HomoloGene: 22697; GeneCards: CHRM5; OMA:CHRM5 - orthologs
Gene location (Human)
Chr.	Chromosome 15 (human)
End	34,067,458 bp
Gene location (Mouse)
Chr.	Chromosome 2 (mouse)
End	112,311,114 bp
RNA expression pattern
	Top expressed in
	testicle; ; corpus callosum; ; C1 segment; ; gonad; ; substantia nigra; ; hypothalamus; ; inferior ganglion of vagus nerve; ; placenta; ; prefrontal cortex; ; right lobe of liver;
	Top expressed in
	ventromedial nucleus; ; mammillary body; ; subiculum; ; ventral tegmental area; ; lateral hypothalamus; ; amygdala; ; anterior amygdaloid area; ; arcuate nucleus; ; dentate gyrus of hippocampal formation granule cell; ; hippocampus proper;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	G protein-coupled receptor activity; signal transducer activity; phosphatidylinositol phospholipase C activity; G protein-coupled acetylcholine receptor activity; G protein-coupled serotonin receptor activity; neurotransmitter receptor activity;
Cellular component	integral component of membrane; postsynaptic membrane; membrane; plasma membrane; synapse; integral component of plasma membrane; cell junction; dendrite;
Biological process	G protein-coupled acetylcholine receptor signaling pathway; regulation of phosphatidylinositol dephosphorylation; gastric acid secretion; transmission of nerve impulse; synaptic transmission, cholinergic; adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway; dopamine transport; phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway; cell population proliferation; signal transduction; G protein-coupled receptor signaling pathway; G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; chemical synaptic transmission; G protein-coupled serotonin receptor signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	1133
	213788
	ENSG00000184984
	ENSMUSG00000074939
	P08912
	Q920H4
	NM_012125; NM_001320917
	NM_205783
	NP_001307846; NP_036257
	NP_991352
	Wikidata
View/Edit Human	View/Edit Mouse

The human muscarinic acetylcholine receptor M₅, encoded by the CHRM5 gene, is a member of the G protein-coupled receptor superfamily of integral membrane proteins. It is coupled to G_q protein.^[5] Binding of the endogenous ligand acetylcholine to the M₅ receptor triggers a number of cellular responses such as adenylate cyclase inhibition, phosphoinositide degradation, and potassium channel modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease cyclic AMP levels and downregulate the activity of protein kinase A (PKA).

Ligands

No highly selective agonists or antagonists for the M₅ receptor have been discovered as of 2018, but several non-selective muscarinic agonists and antagonists have significant affinity for M₅.

The lack of selective M5 receptor ligands is one of the main reasons that the medical community has such a limited understanding of the M5 receptors effects as the possibility that any and/or all effects of non-selective ligands may be due to interactions with other receptors can not be ruled out. Some data may be obtained by observing which effects are common among semi-selective ligands (ex. a ligand of M1 and M5, a ligand of M2 and M5, and a ligand of M3 and M5), but until both a selective agonist and a selective antagonist of the M5 receptor are developed this data must be considered merely theoretical.

Agonists

Milameline ((E)-1,2,5,6-Tetrahydro-1-methyl-3-pyridinecarboxaldehyde-O-methyloxime, CAS# 139886-32-1)
Sabcomeline

Positive allosteric modulators

ML-380^[6]
ML-326^[7]
VU-0238429: EC₅₀ = 1.16 μM; >30-fold selectivity versus M1 and M3, inactive at M2 and M4.^[8]

Negative allosteric modulators

ML375^[9]
VU6008667^[10]

Antagonists

VU-0488130 (ML381)^[11]
Xanomeline^[12]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000184984 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000074939 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology. 7 (10): 740–7. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
^ Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A, et al. (September 2014). "Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)". Journal of Medicinal Chemistry. 57 (18): 7804–10. doi:10.1021/jm500995y. PMC 4175000. PMID 25147929.
^ Gentry PR, Bridges TM, Lamsal A, Vinson PN, Smith E, Chase P, et al. (May 2013). "Discovery of ML326: The first sub-micromolar, selective M5 PAM". Bioorganic & Medicinal Chemistry Letters. 23 (10): 2996–3000. doi:10.1016/j.bmcl.2013.03.032. PMC 3634896. PMID 23562060.
^ Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, et al. (June 2009). "Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins". Journal of Medicinal Chemistry. 52 (11): 3445–8. doi:10.1021/jm900286j. PMC 3875304. PMID 19438238.
^ Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, et al. (November 2013). "Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)". Journal of Medicinal Chemistry. 56 (22): 9351–5. doi:10.1021/jm4013246. PMC 3876027. PMID 24164599.
^ McGowan KM, Nance KD, Cho HP, Bridges TM, Conn PJ, Jones CK, Lindsley CW (March 2017). "5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies". Bioorganic & Medicinal Chemistry Letters. 27 (6): 1356–1359. doi:10.1016/j.bmcl.2017.02.020. PMC 5508536. PMID 28237763.
^ Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P, et al. (August 2014). "Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe". ChemMedChem. 9 (8): 1677–82. doi:10.1002/cmdc.201402051. PMC 4116439. PMID 24692176.
^ Grant MK, El-Fakahany EE (October 2005). "Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor". The Journal of Pharmacology and Experimental Therapeutics. 315 (1): 313–9. doi:10.1124/jpet.105.090134. PMID 16002459.

Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV (1994). "Muscarinic acetylcholine receptor subtypes: localization and structure/function". Progress in Brain Research. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. PMID 8248499.
Gutkind JS, Novotny EA, Brann MR, Robbins KC (June 1991). "Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes". Proceedings of the National Academy of Sciences of the United States of America. 88 (11): 4703–7. Bibcode:1991PNAS...88.4703G. doi:10.1073/pnas.88.11.4703. PMC 51734. PMID 1905013.
Liao CF, Themmen AP, Joho R, Barberis C, Birnbaumer M, Birnbaumer L (May 1989). "Molecular cloning and expression of a fifth muscarinic acetylcholine receptor". The Journal of Biological Chemistry. 264 (13): 7328–37. PMID 2540186.
Bonner TI, Young AC, Brann MR, Buckley NJ (July 1988). "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.
Crespo P, Xu N, Daniotti JL, Troppmair J, Rapp UR, Gutkind JS (August 1994). "Signaling through transforming G protein-coupled receptors in NIH 3T3 cells involves c-Raf activation. Evidence for a protein kinase C-independent pathway". The Journal of Biological Chemistry. 269 (33): 21103–9. PMID 8063729.
Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H (February 1996). "Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C". The Journal of Biological Chemistry. 271 (5): 2776–82. doi:10.1074/jbc.271.5.2776. PMID 8576254.
Kohn EC, Alessandro R, Probst J, Jacobs W, Brilley E, Felder CC (July 1996). "Identification and molecular characterization of a m5 muscarinic receptor in A2058 human melanoma cells. Coupling to inhibition of adenylyl cyclase and stimulation of phospholipase A2". The Journal of Biological Chemistry. 271 (29): 17476–84. doi:10.1074/jbc.271.29.17476. PMID 8663391.
Burstein ES, Spalding TA, Brann MR (September 1998). "The second intracellular loop of the m5 muscarinic receptor is the switch which enables G-protein coupling". The Journal of Biological Chemistry. 273 (38): 24322–7. doi:10.1074/jbc.273.38.24322. PMID 9733718.
Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K (April 1999). "Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines". Neuroscience Letters. 266 (1): 17–20. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173.
Wang H, Han H, Zhang L, Shi H, Schram G, Nattel S, Wang Z (May 2001). "Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart". Molecular Pharmacology. 59 (5): 1029–36. doi:10.1124/mol.59.5.1029. PMID 11306684.
Buchli R, Ndoye A, Arredondo J, Webber RJ, Grando SA (December 2001). "Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes". Molecular and Cellular Biochemistry. 228 (1–2): 57–72. doi:10.1023/A:1013368509855. PMID 11855742.
Fujii T, Watanabe Y, Inoue T, Kawashima K (April 2003). "Upregulation of mRNA encoding the M5 muscarinic acetylcholine receptor in human T- and B-lymphocytes during immunological responses". Neurochemical Research. 28 (3–4): 423–9. doi:10.1023/A:1022840416292. PMID 12675126.
De Luca V, Wang H, Squassina A, Wong GW, Yeomans J, Kennedy JL (2004). "Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia". Neuropsychobiology. 50 (2): 124–7. doi:10.1159/000079102. PMID 15292665.
Qu J, Zhou X, Xie R, Zhang L, Hu D, Li H, Lu F (2006). "The presence of m1 to m5 receptors in human sclera: evidence of the sclera as a potential site of action for muscarinic receptor antagonists". Current Eye Research. 31 (7–8): 587–97. doi:10.1080/02713680600770609. PMID 16877267.
Anney RJ, Lotfi-Miri M, Olsson CA, Reid SC, Hemphill SA, Patton GC (July 2007). "Variation in the gene coding for the M5 muscarinic receptor (CHRM5) influences cigarette dose but is not associated with dependence to drugs of addiction: evidence from a prospective population based cohort study of young adults". BMC Genetics. 8: 46. doi:10.1186/1471-2156-8-46. PMC 1978498. PMID 17608938.{{cite journal}}: CS1 maint: unflagged free DOI (link)

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

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000184984 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000074939 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[Kou_Qin-5] Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology. 7 (10): 740–7. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.

[pmid25147929-6] Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A, et al. (September 2014). "Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)". Journal of Medicinal Chemistry. 57 (18): 7804–10. doi:10.1021/jm500995y. PMC 4175000. PMID 25147929.

[pmid23562060-7] Gentry PR, Bridges TM, Lamsal A, Vinson PN, Smith E, Chase P, et al. (May 2013). "Discovery of ML326: The first sub-micromolar, selective M5 PAM". Bioorganic & Medicinal Chemistry Letters. 23 (10): 2996–3000. doi:10.1016/j.bmcl.2013.03.032. PMC 3634896. PMID 23562060.

[pmid19438238-8] Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, et al. (June 2009). "Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins". Journal of Medicinal Chemistry. 52 (11): 3445–8. doi:10.1021/jm900286j. PMC 3875304. PMID 19438238.

[pmid24164599-9] Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, et al. (November 2013). "Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)". Journal of Medicinal Chemistry. 56 (22): 9351–5. doi:10.1021/jm4013246. PMC 3876027. PMID 24164599.

[10] McGowan KM, Nance KD, Cho HP, Bridges TM, Conn PJ, Jones CK, Lindsley CW (March 2017). "5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies". Bioorganic & Medicinal Chemistry Letters. 27 (6): 1356–1359. doi:10.1016/j.bmcl.2017.02.020. PMC 5508536. PMID 28237763.

[pmid24692176-11] Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P, et al. (August 2014). "Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe". ChemMedChem. 9 (8): 1677–82. doi:10.1002/cmdc.201402051. PMC 4116439. PMID 24692176.

[pmid16002459-12] Grant MK, El-Fakahany EE (October 2005). "Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor". The Journal of Pharmacology and Experimental Therapeutics. 315 (1): 313–9. doi:10.1124/jpet.105.090134. PMID 16002459.

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