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.[1] Multiple alternatively spliced transcript variants have been described for this gene.[1]

## Contents

* 1 Function
* 1.1 Heart
* 1.2 IQ
* 1.3 Olfactory behavior
* 2 Mechanism of action
* 3 Ligands
* 3.1 Agonists
* 3.2 Antagonists
* 4 See also
* 5 References
* 6 Further reading
* 7 External links

## 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 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

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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.[2] A similar association was found independently in the Minnesota Twin and Family Study.[3][4]

However, a larger 2009 study attempting to replicate this claim instead found no significant association between the CHRM2 gene and intelligence.[5]

### Olfactory behavior

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Mediating olfactory guided behaviors (e.g. odor discrimination, aggression, mating).[6]

## 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 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 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

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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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* (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
* Iper-8-naph (compound 8b, bitopic/dualsteric agonist)[11][12]
* Methacholine

### Antagonists

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* AFDX-384
* Atropine[8]
* Chlorpromazine
* Dicycloverine[8]
* Dimenhydrinate
* Dimethindene
* Diphenhydramine
* Gallamine
* Hyoscyamine[13]
* Ipratropium[8]
* Methoctramine[14]
* Otenzepad
* Oxybutynin[8]
* Thorazine
* Tolterodine[8]
* Tripitramine

## See also

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* Muscarinic acetylcholine receptor

## References

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1. ↑ 1.0 1.1 "Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2".
2. ↑ 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.
3. ↑ 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.
4. ↑ 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.
5. ↑ 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.
6. ↑ 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.
7. ↑ 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.
8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
9. ↑ Boron WF, Boulpaep EL (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". Journal of Medicinal Chemistry. 49 (6): 1925–31. doi:10.1021/jm0510878. PMID 16539379.
11. ↑ 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.
12. ↑ 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.
13. ↑ 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
14. ↑ 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

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* Goyal RK (October 1989). "Muscarinic receptor subtypes. Physiology and clinical implications". The New England Journal of Medicine. 321 (15): 1022–9. doi:10.1056/NEJM198910123211506. PMID 2674717.
* Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV (1994). "Muscarinic acetylcholine receptor subtypes: localization and structure/function". Progress in Brain Research. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. 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): 20887–92. 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): 146–50. doi:10.1038/340146a0. PMID 2739737.
* Bonner TI, Buckley NJ, Young AC, Brann MR (July 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, 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): 3923–9. PMC 553870. 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): 489–90. doi:10.1007/BF00360666. PMID 7579899.
* 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): 15175–80. doi:10.1074/jbc.270.25.15175. 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): 2343–51. doi:10.1128/mcb.14.4.2343. PMC 358601. 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): 1099–105. 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): 2776–82. doi:10.1074/jbc.271.5.2776. 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): 1487–95. doi:10.1021/bi962554d. 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): 755–69. doi:10.1016/S0306-4522(97)00524-1. PMID 9579781.
* 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): 14538–44. doi:10.1074/jbc.273.23.14538. 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. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173.
* 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): 2015–20. PMID 10544184.
* 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. doi:10.1159/000028378. PMID 10895079.
* 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. 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 (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.

## External links

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* "Acetylcholine receptors (muscarinic): M2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
* CHRM2+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)

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

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Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin-like

| Neurotransmitter|

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|

Smoothened|

* Smoothened

* v
* t
* e

Muscarinic acetylcholine receptor modulators

mAChRs|

| Agonists|

* 77-LH-28-1
* AC-42
* AC-260,584
* Aceclidine
* Acetylcholine
* AF30
* AF150(S)
* AF267B
* Alvameline
* AQRA-741
* Arecoline
* Bethanechol
* Bevonium
* Butyrylcholine
* Carbachol
* CDD-0034
* CDD-0078
* CDD-0097
* CDD-0098
* CDD-0102
* Cevimeline
* Choline
* cis-Dioxolane
* Clozapine
* Desmethylclozapine (norclozapine)
* Ethoxysebacylcholine
* Itameline
* LY-593,039
* L-689,660
* LY-2,033,298
* McNA343
* Methacholine
* Milameline
* Muscarine
* NGX-267
* Ocvimeline
* Oxotremorine
* PD-151,832
* Pilocarpine
* RS86
* Sabcomeline
* SDZ 210-086
* Sebacylcholine
* Suberyldicholine
* Talsaclidine
* Tazomeline
* Thiopilocarpine
* Vedaclidine
* VU-0029767
* VU-0090157
* VU-0152099
* VU-0152100
* VU-0238429
* WAY-132,983
* Xanomeline
* YM-796

|

Antagonists|

* 3-Quinuclidinyl benzilate
* 4-DAMP
* Aclidinium bromide (+formoterol)
* Abediterol
* AF-DX 250
* AF-DX 384
* Ambutonium bromide
* Anisodamine
* Anisodine
* Antihistamines (first-generation) (e.g., brompheniramine, buclizine, captodiame, chlorphenamine (chlorpheniramine), cinnarizine, clemastine, cyproheptadine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, meclizine, mepyramine (pyrilamine), mequitazine, perlapine, phenindamine, pheniramine, phenyltoloxamine, promethazine, propiomazine, triprolidine)
* AQ-RA 741
* Atropine
* Atropine methonitrate
* Atypical antipsychotics (e.g., clozapine, fluperlapine, olanzapine (+fluoxetine), rilapine, quetiapine, tenilapine, zotepine)
* Benactyzine
* Benzatropine (benztropine)
* Benzilone
* Benzilylcholine mustard
* Benzydamine
* BIBN 99
* Biperiden
* Bornaprine
* Camylofin
* CAR-226,086
* CAR-301,060
* CAR-302,196
* CAR-302,282
* CAR-302,368
* CAR-302,537
* CAR-302,668
* Caramiphen
* Cimetropium bromide
* Clidinium bromide
* Cloperastine
* CS-27349
* Cyclobenzaprine
* Cyclopentolate
* Darifenacin
* DAU-5884
* Desfesoterodine
* Dexetimide
* DIBD
* Dicycloverine (dicyclomine)
* Dihexyverine
* Difemerine
* Diphemanil metilsulfate
* Ditran
* EA-3167
* EA-3443
* EA-3580
* EA-3834
* Emepronium bromide
* Etanautine
* Etybenzatropine (ethybenztropine)
* Fenpiverinium
* Fentonium bromide
* Fesoterodine
* Flavoxate
* Glycopyrronium bromide (+beclometasone/formoterol, +indacaterol)
* Hexahydrodifenidol
* Hexahydrosiladifenidol
* Hexbutinol
* Hexocyclium
* Himbacine
* HL-031,120
* Homatropine
* Imidafenacin
* Ipratropium bromide (+salbutamol)
* Isopropamide
* J-104,129
* Hyoscyamine
* Mamba toxin 3
* Mamba toxin 7
* Mazaticol
* Mebeverine
* Meladrazine
* Mepenzolate
* Methantheline
* Methoctramine
* Methylatropine
* Methylhomatropine
* Methylscopolamine
* Metixene
* Muscarinic toxin 7
* N-Ethyl-3-piperidyl benzilate
* N-Methyl-3-piperidyl benzilate
* Nefopam
* Octatropine methylbromide (anisotropine methylbromide)
* Orphenadrine
* Otenzepad (AF-DX 116)
* Otilonium bromide
* Oxapium iodide
* Oxitropium bromide
* Oxybutynin
* Oxyphencyclimine
* Oxyphenonium bromide
* PBID
* PD-102,807
* PD-0298029
* Penthienate
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* pFHHSiD
* Phenglutarimide
* Phenyltoloxamine
* Pipenzolate bromide
* Piperidolate
* Pirenzepine
* Piroheptine
* Pizotifen
* Poldine
* Pridinol
* Prifinium bromide
* Procyclidine
* Profenamine (ethopropazine)
* Propantheline bromide
* Propiverine
* Quinidine
* Revefenacin
* Rociverine
* RU-47,213
* SCH-57,790
* SCH-72,788
* SCH-217,443
* Scopolamine (hyoscine)
* Scopolamine butylbromide (hyoscine butylbromide)
* Silahexacyclium
* Sofpironium bromide
* Solifenacin
* SSRIs (e.g., femoxetine, paroxetine)
* Telenzepine
* Terodiline
* Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin, mirtazapine)
* Tiemonium iodide
* Timepidium bromide
* Tiotropium bromide
* Tiquizium bromide
* Tofenacin
* Tolterodine
* Tricyclic antidepressants (e.g., amitriptyline (+perphenazine), amitriptylinoxide, butriptyline, cidoxepin, clomipramine, desipramine, desmethyldesipramine, dibenzepin, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nitroxazepine, northiaden (desmethyldosulepin), nortriptyline, protriptyline, quinupramine, trimipramine)
* Tridihexethyl
* Trihexyphenidyl
* Trimebutine
* Tripitamine (tripitramine)
* Tropacine
* Tropatepine
* Tropicamide
* Trospium chloride
* Typical antipsychotics (e.g., chlorpromazine, chlorprothixene, cyamemazine (cyamepromazine), loxapine, mesoridazine, thioridazine)
* Umeclidinium bromide (+vilanterol)
* WIN-2299
* Xanomeline
* Zamifenacin

Precursors
(and prodrugs)|

* Acetyl-coA
* Adafenoxate
* Choline (lecithin)
* Citicoline
* Cyprodenate
* Dimethylethanolamine
* Glycerophosphocholine
* Meclofenoxate (centrophenoxine)
* Phosphatidylcholine
* Phosphatidylethanolamine
* Phosphorylcholine
* Pirisudanol

See also: Receptor/signaling modulators • Nicotinic acetylcholine receptor modulators • Acetylcholine metabolism/transport modulators
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*[mAChRs]: Muscarinic acetylcholine receptors
*[SSRIs]: Selective serotonin reuptake inhibitors