Muscarinic acetylcholine receptor M2

CHRM2
3uon.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCHRM2, HM2, cholinergic receptor muscarinic 2
External IDsMGI: 88397 HomoloGene: 20190 GeneCards: CHRM2
Gene location (Human)
Chromosome 7 (human)
Chr.Chromosome 7 (human)[1]
Chromosome 7 (human)
Genomic location for CHRM2
Genomic location for CHRM2
Band7q33Start136,868,669 bp[1]
End137,020,255 bp[1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_203491

RefSeq (protein)

NP_987076

Location (UCSC)Chr 7: 136.87 – 137.02 MbChr 6: 36.39 – 36.53 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] Multiple alternatively spliced transcript variants have been described for this gene.[5]

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 positive stimulatory actions of the parasympathetic 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 little effect on the contractile forces of the ventricular muscle, slightly decreasing force.

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.[6] A similar association was found independently in the Minnesota Twin and Family Study.[7][8]

However, a larger 2009 study attempting to replicate this claim instead found no significant association between the CHRM2 gene and intelligence.[9]

Olfactory behavior[edit]

Mediating olfactory guided behaviors (e.g. odor discrimination, aggression, mating).[10]

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.[11]

In addition, they modulate muscarinic potassium channels.[12][13] In the heart, this contributes to a decreased heart rate. They do so by the Gβγ subunit of the G protein; Gβγ opens 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]

  • (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)[14]
  • Berberine
  • Iper-8-naph (compound 8b, bitopic/dualsteric agonist)[15][16]
  • Methacholine

Antagonists[edit]

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000181072 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000045613 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
  5. ^ a b "Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2".
  6. ^ 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): 577–84. doi:10.1111/j.1601-183X.2006.00211.x. PMID 17081262.
  7. ^ 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): 10–1. doi:10.1038/sj.mp.4001095. PMID 12556901.
  8. ^ 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". Behavior Genetics. 37 (2): 265–72. doi:10.1007/s10519-006-9131-2. PMID 17160701.
  9. ^ 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". Behavior Genetics. 39 (5): 513–23. doi:10.1007/s10519-009-9274-z. PMID 19418213.
  10. ^ 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): 10773–85. doi:10.1523/JNEUROSCI.0099-15.2015. PMC 4518052. PMID 26224860.
  11. ^ 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): 960–6. PMID 11714883.
  12. ^ a b c d e f Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
  13. ^ Boron WF, Boulpaep EL (2005). Medical Physiology. Philadelphia: Elsevier Saunders. p. 387. ISBN 1-4160-2328-3.
  14. ^ 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". Journal of Medicinal Chemistry. 49 (6): 1925–31. doi:10.1021/jm0510878. PMID 16539379.
  15. ^ Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, Mohr K, De Amici M, Barocelli E, Bertoni S, Dallanoce C (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: 222–32. doi:10.1016/j.ejmech.2014.01.032. PMID 24534538.
  16. ^ Bock A, Merten N, Schrage R, Dallanoce C, Bätz J, Klöckner J, Schmitz J, Matera C, Simon K, Kebig A, Peters L, Müller A, Schrobang-Ley J, Tränkle C, Hoffmann C, De Amici M, Holzgrabe U, Kostenis E, Mohr K (2012-09-04). "The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling". Nature Communications. 3: 1044. doi:10.1038/ncomms2028. PMC 3658004. PMID 22948826.
  17. ^ Edwards Pharmaceuticals, Inc.; Belcher Pharmaceuticals, Inc. (May 2010), "ED-SPAZ- hyoscyamine sulfate tablet, orally disintegrating", DailyMed, U.S. National Library of Medicine, retrieved January 13, 2013
  18. ^ 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): 117–24. doi:10.1016/0014-2999(87)90509-7. PMID 3436364.

Further reading[edit]

External links[edit]

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