Biology:Muscarinic acetylcholine receptor M5
 Generic protein structure example |
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.[1] 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[2]
- ML-326[3]
- VU-0238429: EC50 = 1.16 μM; >30-fold selectivity versus M1 and M3, inactive at M2 and M4.[4]
Negative allosteric modulators
Antagonists
- VU-0488130 (ML381)[7]
- Xanomeline[8]
- Diphenhydramine
- Doxylamine
See also
References
- ↑ "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology 7 (10): 740–7. August 2011. doi:10.1038/nchembio.642. PMID 21873996.
- ↑ "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. September 2014. doi:10.1021/jm500995y. PMID 25147929.
- ↑ "Discovery of ML326: The first sub-micromolar, selective M5 PAM". Bioorganic & Medicinal Chemistry Letters 23 (10): 2996–3000. May 2013. doi:10.1016/j.bmcl.2013.03.032. PMID 23562060.
- ↑ "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. June 2009. doi:10.1021/jm900286j. PMID 19438238.
- ↑ "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-aisoindol-5(9bH)-one (ML375)"]. Journal of Medicinal Chemistry 56 (22): 9351–5. November 2013. doi:10.1021/jm4013246. PMID 24164599.
- ↑ "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. March 2017. doi:10.1016/j.bmcl.2017.02.020. PMID 28237763.
- ↑ "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. August 2014. doi:10.1002/cmdc.201402051. PMID 24692176.
- ↑ "Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor". The Journal of Pharmacology and Experimental Therapeutics 315 (1): 313–9. October 2005. doi:10.1124/jpet.105.090134. PMID 16002459.
Further reading
- "Chapter 12: Muscarinic acetylcholine receptor subtypes: Localization and structure/Function". Cholinergic Function and Dysfunction. Progress in Brain Research. 98. 1993. pp. 121–7. doi:10.1016/S0079-6123(08)62388-2. ISBN 9780444897176.
- "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. June 1991. doi:10.1073/pnas.88.11.4703. PMID 1905013. Bibcode: 1991PNAS...88.4703G.
- "Molecular cloning and expression of a fifth muscarinic acetylcholine receptor". The Journal of Biological Chemistry 264 (13): 7328–37. May 1989. doi:10.1016/S0021-9258(18)83237-9. PMID 2540186.
- "Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes". Neuron 1 (5): 403–10. July 1988. doi:10.1016/0896-6273(88)90190-0. PMID 3272174.
- "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. August 1994. doi:10.1016/S0021-9258(17)31935-X. PMID 8063729.
- "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. February 1996. doi:10.1074/jbc.271.5.2776. PMID 8576254.
- "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. July 1996. doi:10.1074/jbc.271.29.17476. PMID 8663391.
- "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. September 1998. doi:10.1074/jbc.273.38.24322. PMID 9733718.
- "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. April 1999. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173.
- "Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart". Molecular Pharmacology 59 (5): 1029–36. May 2001. doi:10.1124/mol.59.5.1029. PMID 11306684.
- "Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes". Molecular and Cellular Biochemistry 228 (1–2): 57–72. December 2001. doi:10.1023/A:1013368509855. PMID 11855742.
- "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. April 2003. doi:10.1023/A:1022840416292. PMID 12675126.
- "Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia". Neuropsychobiology 50 (2): 124–7. 2004. doi:10.1159/000079102. PMID 15292665.
- "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. 2006. doi:10.1080/02713680600770609. PMID 16877267.
- "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. July 2007. doi:10.1186/1471-2156-8-46. PMID 17608938.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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