Muscarinic acetylcholine receptor M2 explained

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.^[1] Multiple alternatively spliced transcript variants have been described for this gene.^[1] It is G_i-coupled, reducing intracellular levels of cAMP.

Function

Heart

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

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 G_i, inhibits the β-adrenergic mediated relaxation of the airway smooth muscle. Synergistically, activation of the M₃ receptors, which couple to G_q, stimulates contraction of the airway smooth muscle.^[2]

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.^[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]

Olfactory behavior

Mediating olfactory guided behaviors (e.g. odor discrimination, aggression, mating).^[7]

Mechanism of action

M₂ muscarinic receptors act via a G_i type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. They appear to generally serve as autoreceptors.^[8]

In addition, they modulate G protein-coupled inwardly-rectifying potassium channels.^{[9] [10]} In the heart, this contributes to a decreased heart rate. They do so by the G_βγ subunit of the G protein; G_βγ 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)^[11]
• Berberine
• Iper-8-Naph (alias N-8-Iper, bitopic/dualsteric agonist)^{[12] [13] [14]}
• Methacholine
• PAI (photoswitchable agonist)^[15]

Antagonists

• AFDX-384
• Atropine^[9]
• Chlorpromazine
• Dicycloverine^[9]
• Dimenhydrinate
• Dimethindene
• Diphenhydramine
• Gallamine
• Hyoscyamine
• Ipratropium^[9]
• Methoctramine^[16]
• Otenzepad
• Oxybutynin^[9]
• Thorazine
• Tolterodine^[9]
• Trimipramine

See also

• Muscarinic acetylcholine receptor

Further reading

• Goyal RK . Muscarinic receptor subtypes. Physiology and clinical implications . The New England Journal of Medicine . 321 . 15 . 1022–1029 . October 1989 . 2674717 . 10.1056/NEJM198910123211506 .
• Book: Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV . Chapter 12: Muscarinic acetylcholine receptor subtypes: Localization and structure/Function . Cholinergic Function and Dysfunction . Progress in Brain Research . 1993 . 98 . 121–7 . 8248499 . 10.1016/S0079-6123(08)62388-2 . 9780444897176 .
• van Koppen CJ, Nathanson NM . 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 . December 1990 . 2249995 . 10.1016/S0021-9258(17)45299-9 . free .
• Ashkenazi A, Ramachandran J, Capon DJ . Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes . Nature . 340 . 6229 . 146–150 . July 1989 . 2739737 . 10.1038/340146a0 . 4312544 . 1989Natur.340..146A .
• Bonner TI, Buckley NJ, Young AC, Brann MR . Identification of a family of muscarinic acetylcholine receptor genes . Science . 237 . 4814 . 527–532 . July 1987 . 3037705 . 10.1126/science.3037705 . 1987Sci...237..527B .
• Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ . Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors . The EMBO Journal . 6 . 13 . 3923–3929 . December 1987 . 3443095 . 553870 . 10.1002/j.1460-2075.1987.tb02733.x .
• Badner JA, Yoon SW, Turner G, Bonner TI, Detera-Wadleigh SD . Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene . Mammalian Genome . 6 . 7 . 489–490 . July 1995 . 7579899 . 10.1007/BF00360666 . 6934445 .
• Offermanns S, Simon MI . 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 . June 1995 . 7797501 . 10.1074/jbc.270.25.15175 . free .
• Russell M, Winitz S, Johnson GL . Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity . Molecular and Cellular Biology . 14 . 4 . 2343–2351 . April 1994 . 8139539 . 358601 . 10.1128/mcb.14.4.2343 .
• Kunapuli P, Onorato JJ, Hosey MM, Benovic JL . Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5 . The Journal of Biological Chemistry . 269 . 2 . 1099–1105 . January 1994 . 8288567 . 10.1016/S0021-9258(17)42226-5 . free .
• Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H . 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 . February 1996 . 8576254 . 10.1074/jbc.271.5.2776 . free .
• Kostenis E, Conklin BR, Wess J . 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 . February 1997 . 9063897 . 10.1021/bi962554d .
• Smiley JF, Levey AI, Mesulam MM . 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 . June 1998 . 9579781 . 10.1016/S0306-4522(97)00524-1 . 25807845 .
• von der Kammer H, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch RM . Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors . The Journal of Biological Chemistry . 273 . 23 . 14538–14544 . June 1998 . 9603968 . 10.1074/jbc.273.23.14538 . free .
• Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K . 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 . April 1999 . 10336173 . 10.1016/S0304-3940(99)00259-1 . 43548155 .
• Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E . 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 . November 1999 . 10544184 . 10.1096/fasebj.13.14.2015 . free . 38193046 .
• Waid DK, Chell M, El-Fakahany EE . M(2) and M(4) muscarinic receptor subtypes couple to activation of endothelial nitric oxide synthase . Pharmacology . 61 . 1 . 37–42 . July 2000 . 10895079 . 10.1159/000028378 . 43492985 .
• Obara K, Arai K, Miyajima N, Hatano A, Tomita Y, Takahashi K . Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells . Urological Research . 28 . 3 . 196–200 . June 2000 . 10929429 . 10.1007/s002400000113 . 25697686 .
• Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, Mohr K, De Amici M, Barocelli E, Bertoni S, Dallanoce C . 6 . 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 . March 2014 . 24534538 . 10.1016/j.ejmech.2014.01.032 .

External links

• Web site: Acetylcholine receptors (muscarinic): M₂ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-11-25 . 2015-01-02 . https://web.archive.org/web/20150102105826/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2141 . dead .

Notes and References

1. Web site: Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2.
2. Hirshman CA, Lande B, Croxton TL . Role of M2 muscarinic receptors in airway smooth muscle contraction . Life Sciences . 64 . 6–7 . 443–448 . January 1999 . 10069508 . 10.1016/S0024-3205(98)00586-4 . free .
3. Gosso MF, van Belzen M, de Geus EJ, Polderman JC, Heutink P, Boomsma DI, Posthuma D . Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families . Genes, Brain and Behavior . 5 . 8 . 577–584 . November 2006 . 17081262 . 10.1111/j.1601-183X.2006.00211.x . free .
4. Comings DE, Wu S, Rostamkhani M, McGue M, Lacono WG, Cheng LS, MacMurray JP . Role of the cholinergic muscarinic 2 receptor (CHRM2) gene in cognition . Molecular Psychiatry . 8 . 1 . 10–11 . January 2003 . 12556901 . 10.1038/sj.mp.4001095 . 22314941 .
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 . 6 . Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence . Behavior Genetics . 37 . 2 . 265–272 . March 2007 . 17160701 . 10.1007/s10519-006-9131-2 . 9353852 .
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 . 6 . No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples . Behavior Genetics . 39 . 5 . 513–523 . September 2009 . 19418213 . 10.1007/s10519-009-9274-z . 2523697 .
7. Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, Araneda RC . Differential Muscarinic Modulation in the Olfactory Bulb . The Journal of Neuroscience . 35 . 30 . 10773–10785 . July 2015 . 26224860 . 4518052 . 10.1523/JNEUROSCI.0099-15.2015 .
8. Douglas CL, Baghdoyan HA, Lydic R . M2 muscarinic autoreceptors modulate acetylcholine release in prefrontal cortex of C57BL/6J mouse . The Journal of Pharmacology and Experimental Therapeutics . 299 . 3 . 960–966 . December 2001 . 11714883 .
9. Book: Rang HP . Pharmacology . Churchill Livingstone . Edinburgh . 2003 . 0-443-07145-4 .
10. Book: Boron WF, Boulpaep EL . Medical Physiology . Elsevier Saunders . Philadelphia . 2005 . 387 . 1-4160-2328-3 .
11. 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 . 6 . 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 . March 2006 . 16539379 . 10.1021/jm0510878 .
12. Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, Mohr K, De Amici M, Barocelli E, Bertoni S, Dallanoce C . 6 . 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 . March 2014 . 24534538 . 10.1016/j.ejmech.2014.01.032 .
13. Cristofaro I, Spinello Z, Matera C, Fiore M, Conti L, De Amici M, Dallanoce C, Tata AM . 6 . Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells . Neurochemistry International . 118 . 52–60 . September 2018 . 29702145 . 10.1016/j.neuint.2018.04.010 . 207125517 .
14. 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 . 6 . The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling . Nature Communications . 3 . 1044 . 2012-09-04 . 22948826 . 3658004 . 10.1038/ncomms2028 . 2012NatCo...3.1044B .
15. Riefolo F, Matera C, Garrido-Charles A, Gomila AM, Sortino R, Agnetta L, Claro E, Masgrau R, Holzgrabe U, Batlle M, Decker M, Guasch E, Gorostiza P . 6 . Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist . Journal of the American Chemical Society . 141 . 18 . 7628–7636 . May 2019 . 31010281 . 10.1021/jacs.9b03505 . free . 128361100 . 2445/147236 .
16. Melchiorre C, Angeli P, Lambrecht G, Mutschler E, Picchio MT, Wess J . 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 . December 1987 . 3436364 . 10.1016/0014-2999(87)90509-7 .