Muscarinic acetylcholine receptor M2

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Cholinergic receptor, muscarinic 2
3uon.png
Human M2 muscarinic acetylcholine receptor/lysozyme fusion protein. PDB 3uon[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CHRM2 ; HM2
External IDs OMIM118493 MGI88397 HomoloGene20190 IUPHAR: M2 ChEMBL: 211 GeneCards: CHRM2 Gene
Orthologs
Species Human Mouse
Entrez 1129 243764
Ensembl ENSG00000181072 ENSMUSG00000045613
UniProt P08172 Q9ERZ4
RefSeq (mRNA) NM_000739 NM_203491
RefSeq (protein) NP_000730 NP_987076
Location (UCSC) Chr 7:
136.55 – 136.71 Mb
Chr 6:
36.39 – 36.53 Mb
PubMed search [1] [2]

The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor that in humans is encoded by the CHRM2 gene.[2] Multiple alternatively spliced transcript variants have been described for this gene.[2]

Function[edit]

Heart[edit]

The M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after stimulatory actions of the sympathetic nervous system, by slowing the speed of depolarization. They also reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). However, they have no effect on the contractile forces of the ventricular muscle.

IQ[edit]

A Dutch family study found that there is "a highly significant association" between the CHRM2 gene and intelligence as measured by the Wechsler Adult Intelligence Scale-Revised.[3] A similar association was found independently in the Minnesota Twin and Family Study.[4][5]

However, a larger 2009 study attempting to replicate this claim instead found no significant association between the CHRM2 gene and intelligence.[6]

Mechanism of action[edit]

M2 muscarinic receptors act via a Gi type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. They appear to serve as autoreceptors.[7]

In addition, they modulate muscarinic potassium channels.[8][9] In the heart, this contributes to a decreased heart rate. They do so by the G bèta gamma subunit of the G protein coupled to M2. This part of the G protein can open K+ channels in the parasympathetic notches in the heart, which causes an outward current of potassium, which slows down the heart rate.

Ligands[edit]

Few highly selective M2 agonists are available at present, although there are several non-selective muscarinic agonists that stimulate M2, and a number of selective M2 antagonists are available.

Agonists[edit]

  • Bethanechol (nonselective muscarinic agonist)
  • (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide (selective for M2 but only partial agonist)[10]
  • Berberine

Antagonists[edit]

See also[edit]

References[edit]

  1. ^ Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T, Kobayashi T (February 2012). "Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist". Nature 482 (7386): 547–51. doi:10.1038/nature10753. PMC 3345277. PMID 22278061. 
  2. ^ a b "Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2". 
  3. ^ 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 Behav. 5 (8): 577–84. doi:10.1111/j.1601-183X.2006.00211.x. PMID 17081262. 
  4. ^ 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". Mol. Psychiatry 8 (1): 10–1. doi:10.1038/sj.mp.4001095. PMID 12556901. 
  5. ^ Dick DM, Aliev F, Kramer J, Wang JC, Hinrichs A, Bertelsen S, Kuperman S, Schuckit M, Nurnberger J, Edenberg HJ, Porjesz B, Begleiter H, Hesselbrock V, Goate A, Bierut L (March 2007). "Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence". Behav. Genet. 37 (2): 265–72. doi:10.1007/s10519-006-9131-2. PMID 17160701. 
  6. ^ Lind PA, Luciano M, Horan MA, Marioni RE, Wright MJ, Bates TC, Rabbitt P, Harris SE, Davidson Y, Deary IJ, Gibbons L, Pickles A, Ollier W, Pendleton N, Price JF, Payton A, Martin NG (September 2009). "No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples". Behav. Genet. 39 (5): 513–23. doi:10.1007/s10519-009-9274-z. PMID 19418213. 
  7. ^ Douglas CL, Baghdoyan HA, Lydic R (December 2001). "M2 muscarinic autoreceptors modulate acetylcholine release in prefrontal cortex of C57BL/6J mouse". J. Pharmacol. Exp. Ther. 299 (3): 960–6. PMID 11714883. 
  8. ^ a b c d e f Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. 
  9. ^ Boron, W. F and Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. p. 387. ISBN 1-4160-2328-3. 
  10. ^ Scapecchi S, Matucci R, Bellucci C, Buccioni M, Dei S, Guandalini L, Martelli C, Manetti D, Martini E, Marucci G, Nesi M, Romanelli MN, Teodori E, Gualtieri F (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". J. Med. Chem. 49 (6): 1925–31. doi:10.1021/jm0510878. PMID 16539379. 
  11. ^ Edwards Pharmaceuticals, Inc.; Belcher Pharmaceuticals, Inc. (May 2010), DailyMed, U.S. National Library of Medicine, retrieved January 13, 2013 
  12. ^ 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". Eur. J. Pharmacol. 144 (2): 117–24. doi:10.1016/0014-2999(87)90509-7. PMID 3436364. 

Further reading[edit]

  • Goyal RK; Underhill, Lisa H.; Goyal, Raj K. (1989). "Muscarinic receptor subtypes. Physiology and clinical implications.". N. Engl. J. Med. 321 (15): 1022–9. doi:10.1056/NEJM198910123211506. PMID 2674717. 
  • Brann MR, Ellis J, Jørgensen H, et al. (1994). "Muscarinic acetylcholine receptor subtypes: localization and structure/function.". Prog. Brain Res. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. PMID 8248499. 
  • van Koppen CJ, Nathanson NM (1991). "Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. Analysis of the role of N-glycosylation in receptor expression and function.". J. Biol. Chem. 265 (34): 20887–92. PMID 2249995. 
  • Ashkenazi A, Ramachandran J, Capon DJ (1989). "Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes.". Nature 340 (6229): 146–50. doi:10.1038/340146a0. PMID 2739737. 
  • Bonner TI, Buckley NJ, Young AC, Brann MR (1987). "Identification of a family of muscarinic acetylcholine receptor genes.". Science 237 (4814): 527–32. doi:10.1126/science.3037705. PMID 3037705. 
  • Peralta EG, Ashkenazi A, Winslow JW, et al. (1988). "Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors.". EMBO J. 6 (13): 3923–9. PMC 553870. PMID 3443095. 
  • Badner JA, Yoon SW, Turner G, et al. (1995). "Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene.". Mamm. Genome 6 (7): 489–90. doi:10.1007/BF00360666. PMID 7579899. 
  • Offermanns S, Simon MI (1995). "G alpha 15 and G alpha 16 couple a wide variety of receptors to phospholipase C.". J. Biol. Chem. 270 (25): 15175–80. doi:10.1074/jbc.270.25.15175. PMID 7797501. 
  • Russell M, Winitz S, Johnson GL (1994). "Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity.". Mol. Cell. Biol. 14 (4): 2343–51. doi:10.1128/mcb.14.4.2343. PMC 358601. PMID 8139539. 
  • Kunapuli P, Onorato JJ, Hosey MM, Benovic JL (1994). "Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5.". J. Biol. Chem. 269 (2): 1099–105. PMID 8288567. 
  • Haga K, Kameyama K, Haga T, et al. (1996). "Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C.". J. Biol. Chem. 271 (5): 2776–82. doi:10.1074/jbc.271.5.2776. PMID 8576254. 
  • Kostenis E, Conklin BR, Wess J (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): 1487–95. doi:10.1021/bi962554d. PMID 9063897. 
  • Smiley JF, Levey AI, Mesulam MM (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): 755–69. doi:10.1016/S0306-4522(97)00524-1. PMID 9579781. 
  • von der Kammer H, Mayhaus M, Albrecht C, et al. (1998). "Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors.". J. Biol. Chem. 273 (23): 14538–44. doi:10.1074/jbc.273.23.14538. PMID 9603968. 
  • Sato KZ, Fujii T, Watanabe Y, et al. (1999). "Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines.". Neurosci. Lett. 266 (1): 17–20. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173. 
  • Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E (1999). "Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients.". FASEB J. 13 (14): 2015–20. PMID 10544184. 
  • Waid DK, Chell M, El-Fakahany EE (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. PMID 10895079. 
  • Obara K, Arai K, Miyajima N, et al. (2000). "Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells.". Urol. Res. 28 (3): 196–200. doi:10.1007/s002400000113. PMID 10929429. 
  • Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, Mohr K, De Amici M, Barocelli E, Bertoni S, Dallanoce C (2014). "Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity.". Eur. J. Med. Chem. 75: 222–232. doi:10.1016/j.ejmech.2014.01.032. PMID 24534538. 

External links[edit]

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