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Themuscarinic acetylcholine receptor M2,also known as thecholinergic receptor, muscarinic 2,is amuscarinic acetylcholine receptorthat in humans is encoded by theCHRM2gene.[5]Multiple alternatively spliced transcript variants have been described for this gene.[5]It isGi-coupled, reducing intracellular levels ofcAMP.
Function
editHeart
editThe M2muscarinic receptors are located in the heart, where they act to slow theheart ratedown to normalsinus rhythmafter negative stimulatory actions of theparasympathetic nervous system,by slowing the speed ofdepolarization.They also reduce contractile forces of theatrialcardiac muscle, and reduce conduction velocity of theatrioventricular node(AV node). However, they have little effect on the contractile forces of theventricularmuscle, slightly decreasing force.
Airway smooth muscle
editBoth M2and M3muscarinic receptors are expressed in the smooth muscles of the airway, with the majority of the receptors being the M2type. Activation of the M2receptors, which are coupled to Gi,inhibits the β-adrenergic mediated relaxation of the airway smooth muscle. Synergistically, activation of the M3receptors, which couple to Gq,stimulates contraction of the airway smooth muscle.[6]
IQ
editA Dutch family study found that there is "a highly significant association" between theCHRM2geneand intelligence as measured by the Wechsler Adult Intelligence Scale-Revised.[7]A similar association was found independently in theMinnesota Twin and Family Study.[8][9]
However, a larger 2009 study attempting to replicate this claim instead found no significant association between theCHRM2gene and intelligence.[10]
Olfactory behavior
editMediatingolfactoryguided behaviors (e.g. odor discrimination,aggression,mating).[11]
Mechanism of action
editM2muscarinic receptors act via aGitype receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. They appear to generally serve as autoreceptors.[12]
In addition, they modulateG protein-coupled inwardly-rectifying potassium channels.[13][14]In the heart, this contributes to a decreased heart rate. They do so by the Gβγsubunit of the G protein; Gβγshifts the open probability of K+channels in the membrane of the cardiac pacemaker cells, which causes an outward current of potassium, effectively hyperpolarizing the membrane, which slows down the heart rate.
Ligands
editFew highly selective M2agonists are available at present, although there are several non-selective muscarinic agonists that stimulate M2,and a number of selective M2antagonists are available.
Agonists
edit- (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide (selective for M2but only partial agonist)[15]
- Berberine
- Iper-8-Naph (alias N-8-Iper, bitopic/dualsteric agonist)[16][17][18]
- Methacholine
- PAI (photoswitchableagonist)[19]
Antagonists
editSee also
editReferences
edit- ^abcGRCh38: Ensembl release 89: ENSG00000181072–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000045613–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.
- ^ab"Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2".
- ^Hirshman CA, Lande B, Croxton TL (January 1999)."Role of M2 muscarinic receptors in airway smooth muscle contraction".Life Sciences.64(6–7): 443–448.doi:10.1016/S0024-3205(98)00586-4.PMID10069508.
- ^Gosso MF, van Belzen M, de Geus EJ, Polderman JC, Heutink P, Boomsma DI, Posthuma D (November 2006)."Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families".Genes, Brain and Behavior.5(8): 577–584.doi:10.1111/j.1601-183X.2006.00211.x.PMID17081262.
- ^Comings DE, Wu S, Rostamkhani M, McGue M, Lacono WG, Cheng LS, MacMurray JP (January 2003). "Role of the cholinergic muscarinic 2 receptor (CHRM2) gene in cognition".Molecular Psychiatry.8(1): 10–11.doi:10.1038/sj.mp.4001095.PMID12556901.S2CID22314941.
- ^Dick DM, Aliev F, Kramer J, Wang JC, Hinrichs A, Bertelsen S, et al. (March 2007). "Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence".Behavior Genetics.37(2): 265–272.doi:10.1007/s10519-006-9131-2.PMID17160701.S2CID9353852.
- ^Lind PA, Luciano M, Horan MA, Marioni RE, Wright MJ, Bates TC, et al. (September 2009). "No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples".Behavior Genetics.39(5): 513–523.doi:10.1007/s10519-009-9274-z.PMID19418213.S2CID2523697.
- ^Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, Araneda RC (July 2015)."Differential Muscarinic Modulation in the Olfactory Bulb".The Journal of Neuroscience.35(30): 10773–10785.doi:10.1523/JNEUROSCI.0099-15.2015.PMC4518052.PMID26224860.
- ^Douglas CL, Baghdoyan HA, Lydic R (December 2001). "M2 muscarinic autoreceptors modulate acetylcholine release in prefrontal cortex of C57BL/6J mouse".The Journal of Pharmacology and Experimental Therapeutics.299(3): 960–966.PMID11714883.
- ^abcdefRang HP (2003).Pharmacology.Edinburgh: Churchill Livingstone.ISBN0-443-07145-4.
- ^Boron WF, Boulpaep EL (2005).Medical Physiology.Philadelphia: Elsevier Saunders. p. 387.ISBN1-4160-2328-3.
- ^Scapecchi S, Matucci R, Bellucci C, Buccioni M, Dei S, Guandalini L, et al. (March 2006). "Highly chiral muscarinic ligands: the discovery of (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide, a potent, functionally selective, M2 partial agonist".Journal of Medicinal Chemistry.49(6): 1925–1931.doi:10.1021/jm0510878.PMID16539379.
- ^Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, et al. (March 2014). "Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity".European Journal of Medicinal Chemistry.75:222–232.doi:10.1016/j.ejmech.2014.01.032.PMID24534538.
- ^Cristofaro I, Spinello Z, Matera C, Fiore M, Conti L, De Amici M, et al. (September 2018). "Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells".Neurochemistry International.118:52–60.doi:10.1016/j.neuint.2018.04.010.PMID29702145.S2CID207125517.
- ^Bock A, Merten N, Schrage R, Dallanoce C, Bätz J, Klöckner J, et al. (2012-09-04)."The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling".Nature Communications.3:1044.Bibcode:2012NatCo...3.1044B.doi:10.1038/ncomms2028.PMC3658004.PMID22948826.
- ^Riefolo F, Matera C, Garrido-Charles A, Gomila AM, Sortino R, Agnetta L, et al. (May 2019). "Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist".Journal of the American Chemical Society.141(18): 7628–7636.doi:10.1021/jacs.9b03505.hdl:2445/147236.PMID31010281.S2CID128361100.
- ^Edwards Pharmaceuticals, Inc., Belcher Pharmaceuticals, Inc. (May 2010),"ED-SPAZ- hyoscyamine sulfate tablet, orally disintegrating",DailyMed,U.S. National Library of Medicine,retrievedJanuary 13,2013
- ^Melchiorre C, Angeli P, Lambrecht G, Mutschler E, Picchio MT, Wess J (December 1987). "Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine".European Journal of Pharmacology.144(2): 117–124.doi:10.1016/0014-2999(87)90509-7.PMID3436364.
Further reading
edit- Goyal RK (October 1989). "Muscarinic receptor subtypes. Physiology and clinical implications".The New England Journal of Medicine.321(15): 1022–1029.doi:10.1056/NEJM198910123211506.PMID2674717.
- Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV (1993). "Chapter 12: Muscarinic acetylcholine receptor subtypes: Localization and structure/Function".Cholinergic Function and Dysfunction.Progress in Brain Research. Vol. 98. pp. 121–7.doi:10.1016/S0079-6123(08)62388-2.ISBN9780444897176.PMID8248499.
- van Koppen CJ, Nathanson NM (December 1990)."Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. Analysis of the role of N-glycosylation in receptor expression and function".The Journal of Biological Chemistry.265(34): 20887–20892.doi:10.1016/S0021-9258(17)45299-9.PMID2249995.
- Ashkenazi A, Ramachandran J, Capon DJ (July 1989). "Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes".Nature.340(6229): 146–150.Bibcode:1989Natur.340..146A.doi:10.1038/340146a0.PMID2739737.S2CID4312544.
- Bonner TI, Buckley NJ, Young AC, Brann MR (July 1987)."Identification of a family of muscarinic acetylcholine receptor genes".Science.237(4814): 527–532.Bibcode:1987Sci...237..527B.doi:10.1126/science.3037705.PMID3037705.
- Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ (December 1987)."Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors".The EMBO Journal.6(13): 3923–3929.doi:10.1002/j.1460-2075.1987.tb02733.x.PMC553870.PMID3443095.
- Badner JA, Yoon SW, Turner G, Bonner TI, Detera-Wadleigh SD (July 1995)."Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene".Mammalian Genome.6(7): 489–490.doi:10.1007/BF00360666.PMID7579899.S2CID6934445.
- Offermanns S, Simon MI (June 1995)."G Alpha 15 and G Alpha 16 couple a wide variety of receptors to phospholipase C".The Journal of Biological Chemistry.270(25): 15175–15180.doi:10.1074/jbc.270.25.15175.PMID7797501.
- Russell M, Winitz S, Johnson GL (April 1994)."Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity".Molecular and Cellular Biology.14(4): 2343–2351.doi:10.1128/mcb.14.4.2343.PMC358601.PMID8139539.
- Kunapuli P, Onorato JJ, Hosey MM, Benovic JL (January 1994)."Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5".The Journal of Biological Chemistry.269(2): 1099–1105.doi:10.1016/S0021-9258(17)42226-5.PMID8288567.
- 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): 2776–2782.doi:10.1074/jbc.271.5.2776.PMID8576254.
- Kostenis E, Conklin BR, Wess J (February 1997). "Molecular basis of receptor/G protein coupling selectivity studied by coexpression of wild type and mutant m2 muscarinic receptors with mutant G Alpha (q) subunits".Biochemistry.36(6): 1487–1495.doi:10.1021/bi962554d.PMID9063897.
- Smiley JF, Levey AI, Mesulam MM (June 1998). "Infracortical interstitial cells concurrently expressing m2-muscarinic receptors, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate-diaphorase in the human and monkey cerebral cortex".Neuroscience.84(3): 755–769.doi:10.1016/S0306-4522(97)00524-1.PMID9579781.S2CID25807845.
- von der Kammer H, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch RM (June 1998)."Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors".The Journal of Biological Chemistry.273(23): 14538–14544.doi:10.1074/jbc.273.23.14538.PMID9603968.
- 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.PMID10336173.S2CID43548155.
- Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E (November 1999)."Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients".FASEB Journal.13(14): 2015–2020.doi:10.1096/fasebj.13.14.2015.PMID10544184.S2CID38193046.
- Waid DK, Chell M, El-Fakahany EE (July 2000). "M(2) and M(4) muscarinic receptor subtypes couple to activation of endothelial nitric oxide synthase".Pharmacology.61(1): 37–42.doi:10.1159/000028378.PMID10895079.S2CID43492985.
- Obara K, Arai K, Miyajima N, Hatano A, Tomita Y, Takahashi K (June 2000). "Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells".Urological Research.28(3): 196–200.doi:10.1007/s002400000113.PMID10929429.S2CID25697686.
- Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, et al. (March 2014). "Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity".European Journal of Medicinal Chemistry.75:222–232.doi:10.1016/j.ejmech.2014.01.032.PMID24534538.
External links
edit- "Acetylcholine receptors (muscarinic): M2".IUPHAR Database of Receptors and Ion Channels.International Union of Basic and Clinical Pharmacology. Archived fromthe originalon 2015-01-02.Retrieved2008-11-25.
- CHRM2+protein,+humanat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- Overview of all the structural information available in thePDBforUniProt:P08172(Muscarinic acetylcholine receptor M2) at thePDBe-KB.
This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.