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 Gq protein.[5] Binding of the endogenousligandacetylcholine 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).
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.
^ abcGRCh38: Ensembl release 89: ENSG00000184984 - Ensembl, May 2017
^ abcGRCm38: 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. PMC3177959. 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. PMC4175000. 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. PMC3634896. 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. PMC3875304. 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. PMC3876027. 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. PMC5508536. 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. PMC4116439. 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. S2CID 11016091.
Further readingEdit
Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV (1994). Muscarinic acetylcholine receptor subtypes: localization and structure/function. Progress in Brain Research. Vol. 98. pp. 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. PMC51734. 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. doi:10.1016/S0021-9258(18)83237-9. 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. S2CID 833230.
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. doi:10.1016/S0021-9258(17)31935-X. 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. S2CID 43548155.
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. S2CID 10788646.
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. S2CID 38866084.
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. S2CID 29032926.
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. S2CID 3218557.
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. PMC1978498. PMID 17608938.
muscarinic, acetylcholine, receptor, human, muscarinic, acetylcholine, receptor, encoded, chrm5, gene, member, protein, coupled, receptor, superfamily, integral, membrane, proteins, coupled, protein, binding, endogenous, ligand, acetylcholine, receptor, trigge. 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 Gq 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 CHRM5IdentifiersAliasesCHRM5 HM5 cholinergic receptor muscarinic 5External IDsOMIM 118496 MGI 109248 HomoloGene 22697 GeneCards CHRM5Gene location Human Chr Chromosome 15 human 1 Band15q14Start33 968 497 bp 1 End34 067 458 bp 1 Gene location Mouse Chr Chromosome 2 mouse 2 Band2 E3 2 57 02 cMStart112 309 516 bp 2 End112 311 114 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed incorpus callosumsubstantia nigrahypothalamusinferior ganglion of vagus nerveplacentaprefrontal cortexright lobe of liverpharynxBrodmann area 9hippocampus properTop expressed inventromedial nucleusmammillary bodysubiculumventral tegmental arealateral hypothalamusamygdalaarcuate nucleushippocampus properdorsomedial hypothalamic nucleussuprachiasmatic nucleusMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionG 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 activityCellular componentintegral component of membrane postsynaptic membrane membrane plasma membrane synapse integral component of plasma membrane cell junction dendriteBiological processG 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 pathwaySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez1133213788EnsemblENSG00000184984ENSMUSG00000074939UniProtP08912Q920H4RefSeq mRNA NM 012125NM 001320917NM 205783RefSeq protein NP 001307846NP 036257NP 991352Location UCSC Chr 15 33 97 34 07 MbChr 2 112 31 112 31 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Ligands 1 1 Agonists 1 2 Positive allosteric modulators 1 3 Negative allosteric modulators 1 4 Antagonists 2 See also 3 References 4 Further readingLigands EditNo 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 Edit Milameline E 1 2 5 6 Tetrahydro 1 methyl 3 pyridinecarboxaldehyde O methyloxime CAS 139886 32 1 SabcomelinePositive allosteric modulators Edit ML 380 6 ML 326 7 VU 0238429 EC50 1 16 mM gt 30 fold selectivity versus M1 and M3 inactive at M2 and M4 8 Negative allosteric modulators Edit ML375 9 VU6008667 10 Antagonists Edit VU 0488130 ML381 11 Xanomeline 12 DiphenhydramineSee also EditMuscarinic acetylcholine receptorReferences Edit 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 amp 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 amp 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 S2CID 11016091 Further reading EditBrann MR Ellis J Jorgensen H Hill Eubanks D Jones SV 1994 Muscarinic acetylcholine receptor subtypes localization and structure function Progress in Brain Research Vol 98 pp 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 doi 10 1016 S0021 9258 18 83237 9 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 S2CID 833230 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 doi 10 1016 S0021 9258 17 31935 X 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 S2CID 43548155 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 S2CID 10788646 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 S2CID 38866084 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 S2CID 29032926 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 S2CID 3218557 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 This article incorporates text from the United States National Library of Medicine which is in the public domain Retrieved from https en wikipedia org w index php title Muscarinic acetylcholine receptor M5 amp oldid 1170973244, wikipedia, wiki, book, books, library,
