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Acetylcholine receptors (muscarinic) C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [13]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates. Of note, it has been observed that mAChRs dimerise reversibly [38] and that dimerisation/oligomerisation can be affected by ligands [61,65].
Receptors
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M1 receptor
C
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M2 receptor
C
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M3 receptor
C
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M4 receptor
C
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M5 receptor
C
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Further reading
* Key recommended reading is highlighted with an asterisk
Abrams P, Andersson KE, Buccafusco JJ, Chapple C, de Groat WC, Fryer AD, Kay G, Laties A, Nathanson NM, Pasricha PJ et al.. (2006) Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol, 148 (5): 565-78. [PMID:16751797]
Andersson KE. (2011) Muscarinic acetylcholine receptors in the urinary tract. Handb Exp Pharmacol, (202): 319-44. [PMID:21290234]
Birdsall NJ, Lazareno S. (2005) Allosterism at muscarinic receptors: ligands and mechanisms. Mini Rev Med Chem, 5 (6): 523-43. [PMID:15974931]
Brown DA. (2010) Muscarinic acetylcholine receptors (mAChRs) in the nervous system: some functions and mechanisms. J Mol Neurosci, 41 (3): 340-6. [PMID:20446119]
* Burger WAC, Sexton PM, Christopoulos A, Thal DM. (2018) Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors. J Gen Physiol, 150 (10): 1360-1372. [PMID:30190312]
* Caulfield MP, Birdsall NJ. (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev, 50 (2): 279-90. [PMID:9647869]
Conn PJ, Christopoulos A, Lindsley CW. (2009) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov, 8 (1): 41-54. [PMID:19116626]
Conn PJ, Jones CK, Lindsley CW. (2009) Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci, 30 (3): 148-55. [PMID:19201489]
De Amici M, Dallanoce C, Holzgrabe U, Tränkle C, Mohr K. (2010) Allosteric ligands for G protein-coupled receptors: a novel strategy with attractive therapeutic opportunities. Med Res Rev, 30 (3): 463-549. [PMID:19557759]
Eckelman WC. (2006) Imaging of muscarinic receptors in the central nervous system. Curr Pharm Des, 12 (30): 3901-13. [PMID:17073686]
Eglen RM. (2005) Muscarinic receptor subtype pharmacology and physiology. Prog Med Chem, 43: 105-36. [PMID:15850824]
Eglen RM. (2006) Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function. Auton Autacoid Pharmacol, 26 (3): 219-33. [PMID:16879488]
* Eglen RM. (2012) Overview of muscarinic receptor subtypes. Handb Exp Pharmacol, (208): 3-28. [PMID:22222692]
Gregory KJ, Sexton PM, Christopoulos A. (2007) Allosteric modulation of muscarinic acetylcholine receptors. Curr Neuropharmacol, 5 (3): 157-67. [PMID:19305798]
Ishii M, Kurachi Y. (2006) Muscarinic acetylcholine receptors. Curr Pharm Des, 12 (28): 3573-81. [PMID:17073660]
* Kruse AC, Kobilka BK, Gautam D, Sexton PM, Christopoulos A, Wess J. (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov, 13 (7): 549-60. [PMID:24903776]
* Leach K, Simms J, Sexton PM, Christopoulos A. (2012) Structure-function studies of muscarinic acetylcholine receptors. Handb Exp Pharmacol, (208): 29-48. [PMID:22222693]
Mohr K, Tränkle C, Kostenis E, Barocelli E, De Amici M, Holzgrabe U. (2010) Rational design of dualsteric GPCR ligands: quests and promise. Br J Pharmacol, 159 (5): 997-1008. [PMID:20136835]
Nathanson NM. (2008) Synthesis, trafficking, and localization of muscarinic acetylcholine receptors. Pharmacol Ther, 119 (1): 33-43. [PMID:18558434]
Peretto I, Petrillo P, Imbimbo BP. (2009) Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists. Med Res Rev, 29 (6): 867-902. [PMID:19399831]
Potter LT, Flynn DD, Liang JS, McCollum MH. (2004) Studies of muscarinic neurotransmission with antimuscarinic toxins. Prog Brain Res, 145: 121-8. [PMID:14650911]
Servent D, Fruchart-Gaillard C. (2009) Muscarinic toxins: tools for the study of the pharmacological and functional properties of muscarinic receptors. J Neurochem, 109 (5): 1193-202. [PMID:19457160]
Tobin G, Giglio D, Lundgren O. (2009) Muscarinic receptor subtypes in the alimentary tract. J Physiol Pharmacol, 60 (1): 3-21. [PMID:19439804]
* Valant C, Robert Lane J, Sexton PM, Christopoulos A. (2012) The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu Rev Pharmacol Toxicol, 52: 153-78. [PMID:21910627]
Wess J, Eglen RM, Gautam D. (2007) Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov, 6 (9): 721-33. [PMID:17762886]
References
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NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Arthur Christopoulos (Chairperson)
Nigel J. M. Birdsall (Past chairperson)
Sophie Bradley
David A. Brown
Frederick Ehlert
Christian C. Felder
Chris Langmead
Fred Mitchelson
Neil M. Nathanson
Andrew B. Tobin
Celine Valant
Jurgen Wess |
Other contributors:
Noel J. Buckley
R.A. John Challiss
Richard M. Eglen
Rudolf Hammer
Heinz J. Kilbinger
Günter Lambrecht
Ernst Mutschler
Roy D. Schwarz
David Thal |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
Atomic structures for all five mAChRs bound to antagonists have been determined [36,100,105,110,118]. Structures of agonist-bound M1, M2, M3, and M4 mAChRs [51,111,117,119] and β2-arrestin-bound M2 mAChR have been reported [98]. These structures show that the orthosteric binding site of this family of receptor is absolutely conserved and, as a consequence, explain why highly selective orthosteric ligand binding to any specific mAChR has been notoriously difficult to achieve. As such, it is common to assess the rank order of affinity for a range of antagonists with limited selectivity (e.g., 4-DAMP, darifenacin, pirenzepine, AFDX384) to identify the involvement of particular subtypes- although caution should be used in the design and interpretation of such experiments due to the lack of absolute ligand subtype selectivity [72]. Some ligands may display selectivity at the level of function (e.g., xanomeline) or binding kinetics (e.g., tiotropium) [84,91,104]. In addition, structures of the M3 and M4 mAChR DREADDS (designer receptors exclusively activated by designer drugs) have been reported providing insights into orthosteric ligand selectivity for these chemogenetic tools [119].
Structures of the M1 and M2 and M4 mAChRs in complex with allosteric modulators [51,63,111] have validated numerous pharmacological studies that indicated the presence of a common mAChR allosteric site located at the extracellular entrance to these receptors. In addition, a structure of the M1 mAChR with muscarinic toxin 7 (MT7) bound to the common allosteric site has provided insight into the extreme subtype selectivity of MT7 [63]. Allosteric ligands proposed to bind to this common allosteric site include gallamine, strychnine, C7/3-phth, brucine and LY2033298. Additionally, a second allosteric site has been proposed on the mAChRs based on pharmacological analyses of the actions of compounds such as KT 5720, WIN 62,577, WIN 51,708, staurosporine and amiodarone [10,57-58,97]. In the presence of the orthosteric ligand, allosteric modulators can exert positive, negative, or neutral cooperativity with that ligand. Direct receptor activation via an allosteric site has been reported for a number of allosteric ligands of the mAChRs [24,59-60,62,73-74]. ‘Atypical agonists’ are ligands that have been suggested to have bitopic binding modes for at least one subtype whereby the agonist occupies both the orthosteric and allosteric sites [4,47,108]. Several mAChR PET radioligands have been reported, but their utility for subtype selectivity measurements in the human brain has yet to be confirmed [79].