Muscarinic acetylcholine receptor M2
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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.
Function
Heart
The M2 muscarinic receptors are located in the heart, where they act to slow the
ventricular
muscle, slightly decreasing force.
Airway smooth muscle
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]
IQ
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
Mediating
Mechanism of action
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
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
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
- (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)[15]
- Berberine
- Iper-8-Naph (alias N-8-Iper, bitopic/dualsteric agonist)[16][17][18]
- Methacholine
- PAI (photoswitchable agonist)[19]
Antagonists
- AFDX-384
- Atropine[13]
- Chlorpromazine
- Dicycloverine[13]
- Dimenhydrinate
- Dimethindene
- Diphenhydramine
- Gallamine
- Hyoscyamine[20]
- Ipratropium[13]
- Methoctramine[21]
- Otenzepad
- Oxybutynin[13]
- Thorazine
- Tolterodine[13]
- Trimipramine
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000181072 – Ensembl, May 2017
- ^ a b c GRCm38: 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.
- ^ a b "Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2".
- PMID 10069508.
- PMID 17081262.
- S2CID 22314941.
- S2CID 9353852.
- S2CID 2523697.
- PMID 26224860.
- PMID 11714883.
- ^ ISBN 0-443-07145-4.
- ISBN 1-4160-2328-3.
- PMID 16539379.
- PMID 24534538.
- S2CID 207125517.
- PMID 22948826.
- S2CID 128361100.
- ^ 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
- PMID 3436364.
Further reading
- Goyal RK (October 1989). "Muscarinic receptor subtypes. Physiology and clinical implications". The New England Journal of Medicine. 321 (15): 1022–1029. PMID 2674717.
- 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. PMID 8248499.
- 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. PMID 2249995.
- 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. S2CID 4312544.
- Bonner TI, Buckley NJ, Young AC, Brann MR (July 1987). "Identification of a family of muscarinic acetylcholine receptor genes". Science. 237 (4814): 527–532. PMID 3037705.
- 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. PMID 3443095.
- 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. S2CID 6934445.
- 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. PMID 7797501.
- 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. PMID 8139539.
- 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. PMID 8288567.
- 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. PMID 8576254.
- 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. PMID 9063897.
- 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. S2CID 25807845.
- 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. PMID 9603968.
- 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. S2CID 43548155.
- 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. S2CID 38193046.
- 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. S2CID 43492985.
- 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. S2CID 25697686.
- 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. PMID 24534538.
External links
- "Acetylcholine receptors (muscarinic): M2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-01-02. Retrieved 2008-11-25.
- CHRM2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P08172 (Muscarinic acetylcholine receptor M2) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.