Muscarinic acetylcholine receptor M2

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] It is Gi-coupled, reducing intracellular levels of cAMP.

CHRM2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCHRM2, HM2, cholinergic receptor muscarinic 2
External IDsOMIM: 118493; MGI: 88397; HomoloGene: 20190; GeneCards: CHRM2; OMA:CHRM2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_203491

RefSeq (protein)

NP_987076

Location (UCSC)Chr 7: 136.87 – 137.02 MbChr 6: 36.37 – 36.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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Heart

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The M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after negative 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.

Airway smooth muscle

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Both M2 and M3 muscarinic receptors are expressed in the smooth muscles of the airway, with the majority of the receptors being the M2 type. Activation of the M2 receptors, which are coupled to Gi, inhibits the β-adrenergic mediated relaxation of the airway smooth muscle. Synergistically, activation of the M3 receptors, which couple to Gq, stimulates contraction of the airway smooth muscle.[6]

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.[7] A similar association was found independently in the Minnesota Twin and Family Study.[8][9]

However, a larger 2009 study attempting to replicate this claim instead found no significant association between the CHRM2 gene and intelligence.[10]

Olfactory behavior

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Mediating olfactory guided behaviors (e.g. odor discrimination, aggression, mating).[11]

Mechanism of action

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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 generally serve as autoreceptors.[12]

In addition, they modulate G protein-coupled inwardly-rectifying potassium channels.[13][14] In the heart, this contributes to a decreased heart rate. They do so by the Gβγ subunit of the G protein; Gβγ shifts 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

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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

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Antagonists

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See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000181072Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000045613Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2".
  6. ^ 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. PMID 10069508.
  7. ^ 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. PMID 17081262.
  8. ^ 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. PMID 12556901. S2CID 22314941.
  9. ^ 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. PMID 17160701. S2CID 9353852.
  10. ^ 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. PMID 19418213. S2CID 2523697.
  11. ^ 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. PMC 4518052. PMID 26224860.
  12. ^ 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. PMID 11714883.
  13. ^ a b c d e f Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
  14. ^ Boron WF, Boulpaep EL (2005). Medical Physiology. Philadelphia: Elsevier Saunders. p. 387. ISBN 1-4160-2328-3.
  15. ^ 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. PMID 16539379.
  16. ^ 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. PMID 24534538.
  17. ^ 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. PMID 29702145. S2CID 207125517.
  18. ^ 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. PMC 3658004. PMID 22948826.
  19. ^ 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. PMID 31010281. S2CID 128361100.
  20. ^ 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
  21. ^ 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. PMID 3436364.

Further reading

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