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{{Wrongtitle|title=Muscarinic acetylcholine receptor M<sub>2</sub>}}
{{Refimprove|date=May 2016}}
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{{DISPLAYTITLE:Muscarinic acetylcholine receptor M<sub>2</sub>}}
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{{Infobox_gene}}
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The '''muscarinic acetylcholine receptor M<sub>2</sub>''', also known as the '''cholinergic receptor, muscarinic 2''', is a [[muscarinic acetylcholine receptor]] that in humans is encoded by the CHRM2 [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1129| accessdate = }}</ref> Multiple alternatively spliced transcript variants have been described for this gene.<ref name="entrez"/>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Cholinergic receptor, muscarinic 2
| HGNCid = 1951
| Symbol = CHRM2
| AltSymbols =; FLJ43243; HM2; MGC120006; MGC120007
| OMIM = 118493
| ECnumber = 
| Homologene = 20190
| MGIid = 88397
| Function = {{GNF_GO|id=GO:0001584 |text = rhodopsin-like receptor activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0004981 |text = muscarinic acetylcholine receptor activity}}
| Component = {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0045211 |text = postsynaptic membrane}}
| Process = {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007188 |text = G-protein signaling, coupled to cAMP nucleotide second messenger}} {{GNF_GO|id=GO:0007197 |text = muscarinic acetylcholine receptor, adenylate cyclase inhibiting pathway}} {{GNF_GO|id=GO:0007207 |text = muscarinic acetylcholine receptor, phospholipase C activating pathway}} {{GNF_GO|id=GO:0007213 |text = acetylcholine receptor signaling, muscarinic pathway}} {{GNF_GO|id=GO:0007399 |text = nervous system development}} {{GNF_GO|id=GO:0008016 |text = regulation of heart contraction}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1129
    | Hs_Ensembl = ENSG00000181072
    | Hs_RefseqProtein = NP_000730
    | Hs_RefseqmRNA = NM_000739
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 7
    | Hs_GenLoc_start = 136203956
    | Hs_GenLoc_end = 136355539
    | Hs_Uniprot = P08172
    | Mm_EntrezGene = 243764
    | Mm_Ensembl = ENSMUSG00000045613
    | Mm_RefseqmRNA = NM_203491
    | Mm_RefseqProtein = NP_987076
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 36453362
    | Mm_GenLoc_end = 36454762
    | Mm_Uniprot = Q05CZ8
  }}
}}
The '''muscarinic acetylcholine receptor M<sub>2</sub>''', also known as the '''cholinergic receptor, muscarinic 2''', is a [[muscarinic acetylcholine receptor]].


==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 stimulatory actions of the sympathetic nervous system, by slowing the speed of [[depolarization]]. They also reduce contractile forces of the [[heart atrium|atrial]] cardiac muscle, and reduce conduction velocity of the [[atrioventricular node]] (AV node). However, they have no effect on the contractile forces of the [[heart ventricle|ventricular]] muscle.


==Mechanism==
The M<sub>2</sub> 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 [[heart atrium|atrial]] cardiac muscle, and reduce conduction velocity of the [[atrioventricular node]] (AV node). However, they have no effect on the contractile forces of the [[heart ventricle|ventricular]] muscle.
M2 muscarinic receptors act via a [[Gi alpha subunit|G<sub>i</sub>]] type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects.


In addition, they modulate [[muscarinic potassium channels]].<ref name=Rang>{{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}} </ref><ref name=Boron> {{cite book |author=Boron, W. F and Boulpaep, E. L. |title=Medical Physiology |publisher=Elsevier Saunders |location=Philadelphia |year=2005 |pages=387 |isbn=1-4160-2328-3 |oclc= |doi=}} </ref> In the heart, this contributes to a decreased heart rate.
=== IQ ===


==Gene==
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.<ref name="pmid17081262">{{cite journal | vauthors = Gosso MF, van Belzen M, de Geus EJ, Polderman JC, Heutink P, Boomsma DI, Posthuma D | title = Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families | journal = Genes Brain Behav. | volume = 5 | issue = 8 | pages = 577–84 | date = November 2006 | pmid = 17081262 | doi = 10.1111/j.1601-183X.2006.00211.x }}</ref> A similar association was found independently in the ''Minnesota Twin and Family Study''.<ref name="pmid12556901">{{cite journal | vauthors = Comings DE, Wu S, Rostamkhani M, McGue M, Lacono WG, Cheng LS, MacMurray JP | title = Role of the cholinergic muscarinic 2 receptor (CHRM2) gene in cognition | journal = Mol. Psychiatry | volume = 8 | issue = 1 | pages = 10–1 | date = January 2003 | pmid = 12556901 | doi = 10.1038/sj.mp.4001095 }}</ref><ref name="pmid17160701">{{cite journal | vauthors = 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 | title = Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence | journal = Behav. Genet. | volume = 37 | issue = 2 | pages = 265–72 | date = March 2007 | pmid = 17160701 | doi = 10.1007/s10519-006-9131-2 }}</ref>
Muscarinic acetylcholine receptor M2 is encoded by the gene {{gene|CHRM2}}.<ref name="entrez">{{cite web | title = Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1129| accessdate = }}</ref>


<!-- The PBB_Summary template is not automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
However, a larger 2009 study attempting to replicate this claim instead found no significant association between the CHRM2 gene and intelligence.<ref name="pmid19418213">{{cite journal | vauthors = 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 | title = No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples | journal = Behav. Genet. | volume = 39 | issue = 5 | pages = 513–23 | date = September 2009 | pmid = 19418213 | doi = 10.1007/s10519-009-9274-z }}</ref>
{{PBB_Summary
| section_title =
| summary_text =Multiple alternatively spliced transcript variants have been described for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1129| accessdate = }}</ref>
}}


==See also==
=== Olfactory behavior ===
Mediating [[Olfaction|olfactory]] guided behaviors (e.g. odor discrimination, [[aggression]], [[mating]]).<ref>{{cite journal | vauthors = Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, Araneda RC | title = Differential Muscarinic Modulation in the Olfactory Bulb | journal = The Journal of Neuroscience | volume = 35 | issue = 30 | pages = 10773–85 | date = Jul 2015 | pmid = 26224860 | doi = 10.1523/JNEUROSCI.0099-15.2015 | pmc=4518052}}</ref>
 
== Mechanism of action ==
 
M<sub>2</sub> muscarinic receptors act via a [[Gi alpha subunit|G<sub>i</sub>]] type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. They appear to serve as autoreceptors.<ref name="pmid11714883">{{cite journal | vauthors = Douglas CL, Baghdoyan HA, Lydic R | title = M2 muscarinic autoreceptors modulate acetylcholine release in prefrontal cortex of C57BL/6J mouse | journal = J. Pharmacol. Exp. Ther. | volume = 299 | issue = 3 | pages = 960–6 | date = December 2001 | pmid = 11714883 | doi =  }}</ref>
 
In addition, they modulate [[muscarinic potassium channels]].<ref name="Rang">{{cite book | author = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}}</ref><ref name="Boron">{{cite book |author1=Boron, W. F  |author2=Boulpaep, E. L.  |lastauthoramp=yes |title=Medical Physiology |publisher=Elsevier Saunders |location=Philadelphia |year=2005 |pages=387 |isbn=1-4160-2328-3 |oclc= |doi=}}</ref> In the heart, this contributes to a decreased heart rate. They do so by the G beta gamma subunit of the G protein coupled to M<sub>2</sub>. This part of the G protein can open K<sup>+</sup> channels in the parasympathetic notches in the heart, which causes an outward current of potassium, which slows down the heart rate.
 
==Ligands==
Few highly selective M<sub>2</sub> agonists are available at present, although there are several non-selective muscarinic agonists that stimulate M<sub>2</sub>, and a number of selective M<sub>2</sub> antagonists are available.
 
===Agonists===
* [[methacholine]] (selective m3 muscarinic agonist)
* Iper-8-naph (compound 8b, bitopic/dualsteric agonist)<ref>{{Cite journal|last=Matera|first=Carlo|last2=Flammini|first2=Lisa|last3=Quadri|first3=Marta|last4=Vivo|first4=Valentina|last5=Ballabeni|first5=Vigilio|last6=Holzgrabe|first6=Ulrike|last7=Mohr|first7=Klaus|last8=De Amici|first8=Marco|last9=Barocelli|first9=Elisabetta|date=2014-03-21|title=Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: Synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity|url=http://www.sciencedirect.com/science/article/pii/S0223523414000786|journal=European Journal of Medicinal Chemistry|volume=75|pages=222–232|doi=10.1016/j.ejmech.2014.01.032|pmid=24534538}}</ref><ref>{{Cite journal|last=Bock|first=Andreas|last2=Merten|first2=Nicole|last3=Schrage|first3=Ramona|last4=Dallanoce|first4=Clelia|last5=Bätz|first5=Julia|last6=Klöckner|first6=Jessica|last7=Schmitz|first7=Jens|last8=Matera|first8=Carlo|last9=Simon|first9=Katharina|date=2012-09-04|title=The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling|url=http://www.nature.com/doifinder/10.1038/ncomms2028|journal=Nature Communications|language=en|volume=3|doi=10.1038/ncomms2028|issn=2041-1723|pmc=3658004|pmid=22948826|page=1044}}</ref>
* (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide (selective for M<sub>2</sub> but only partial agonist)<ref name="pmid16539379">{{cite journal | vauthors = 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 | title = 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 = J. Med. Chem. | volume = 49 | issue = 6 | pages = 1925–31 | date = March 2006 | pmid = 16539379 | doi = 10.1021/jm0510878 | url =  }}</ref>
* [[Berberine]]
 
===Antagonists===
* [[Atropine]]<ref name="Rang"/>
* [[Hyoscyamine]]<ref>{{Citation | last = Edwards Pharmaceuticals, Inc. | first = | author-link = | last2 = Belcher Pharmaceuticals, Inc. | title = ED-SPAZ- hyoscyamine sulfate tablet, orally disintegrating  | work = DailyMed | publisher = U.S. National Library of Medicine | date = May 2010 | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f33a4774-9fbb-4782-a7e1-068e83b7504d | accessdate = January 13, 2013}}</ref>
* [[Dimethindene]] - N,N-Dimethyl-3-[(1S)-1-(2-pyridinyl)ethyl]-1H-indene-2-ethanamine, CAS# 121367-05-3, mixed M<sub>2</sub> / histamine H<sub>1</sub> antagonist
* [[Otenzepad]] - 11-([2-[(Diethylamino)methyl]-1-piperidinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, CAS# 102394-31-0
* AQRA-741 - 11-([4-[4-(Diethylamino)butyl]-1-piperidinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, CAS# 123548-16-3
* [[AFDX-384]] (mixed M2/M4 antagonist) - N-[2-[2-[(Dipropylamino)methyl]-1-piperidinyl]ethyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide, CAS# 118290-27-0
<!-----why were these in the "Muscarinic acetylcholine receptor" article but not nere?----->
*[[dicycloverine]]<ref name=Rang/>
*[[Thorazine]]
*[[Diphenhydramine]]
*[[Dimenhydrinate]]
*[[tolterodine]]<ref name=Rang/>
*[[oxybutynin]]<ref name=Rang/>
*[[ipratropium]]<ref name=Rang/>
*[[methoctramine]]<ref name="pmid3436364">{{cite journal | vauthors = Melchiorre C, Angeli P, Lambrecht G, Mutschler E, Picchio MT, Wess J | title = Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine | journal = Eur. J. Pharmacol. | volume = 144 | issue = 2 | pages = 117–24 | date = December 1987 | pmid = 3436364 | doi = 10.1016/0014-2999(87)90509-7 }}</ref>
*[[tripitramine]]
*[[gallamine]]
*[[chlorpromazine]]
 
== See also ==
* [[Muscarinic acetylcholine receptor]]
* [[Muscarinic acetylcholine receptor]]


==References==
== References ==
{{reflist|2}}
{{reflist|35em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|35em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Goyal RK | title = Muscarinic receptor subtypes. Physiology and clinical implications. | journal = N. Engl. J. Med. | volume = 321 | issue = 15 | pages = 1022–9 | year = 1989 | pmid = 2674717 | doi = 10.1056/NEJM198910123211506 }}
| citations =
* {{cite journal | vauthors = Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV | title = Muscarinic acetylcholine receptor subtypes: localization and structure/function. | journal = Prog. Brain Res. | volume = 98 | issue =  | pages = 121–7 | year = 1994 | pmid = 8248499 | doi = 10.1016/S0079-6123(08)62388-2 }}
*{{cite journal | author=Goyal RK |title=Muscarinic receptor subtypes. Physiology and clinical implications. |journal=N. Engl. J. Med. |volume=321 |issue= 15 |pages= 1022-9 |year= 1989 |pmid= 2674717 |doi= }}
* {{cite journal | vauthors = van Koppen CJ, Nathanson NM | title = Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. Analysis of the role of N-glycosylation in receptor expression and function. | journal = J. Biol. Chem. | volume = 265 | issue = 34 | pages = 20887–92 | year = 1991 | pmid = 2249995 | doi =  }}
*{{cite journal | author=Brann MR, Ellis J, Jørgensen H, ''et al.'' |title=Muscarinic acetylcholine receptor subtypes: localization and structure/function. |journal=Prog. Brain Res. |volume=98 |issue=  |pages= 121-7 |year= 1994 |pmid= 8248499 |doi= }}
* {{cite journal | vauthors = Ashkenazi A, Ramachandran J, Capon DJ | title = Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. | journal = Nature | volume = 340 | issue = 6229 | pages = 146–50 | year = 1989 | pmid = 2739737 | doi = 10.1038/340146a0 }}
*{{cite journal | author=van Koppen CJ, Nathanson NM |title=Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. Analysis of the role of N-glycosylation in receptor expression and function. |journal=J. Biol. Chem. |volume=265 |issue= 34 |pages= 20887-92 |year= 1991 |pmid= 2249995 |doi=  }}
* {{cite journal | vauthors = Bonner TI, Buckley NJ, Young AC, Brann MR | title = Identification of a family of muscarinic acetylcholine receptor genes. | journal = Science | volume = 237 | issue = 4814 | pages = 527–32 | year = 1987 | pmid = 3037705 | doi = 10.1126/science.3037705 }}
*{{cite journal | author=Ashkenazi A, Ramachandran J, Capon DJ |title=Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. |journal=Nature |volume=340 |issue= 6229 |pages= 146-50 |year= 1989 |pmid= 2739737 |doi= 10.1038/340146a0 }}
* {{cite journal | vauthors = Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ | title = Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. | journal = EMBO J. | volume = 6 | issue = 13 | pages = 3923–9 | year = 1988 | pmid = 3443095 | pmc = 553870 | doi =  }}
*{{cite journal | author=Bonner TI, Buckley NJ, Young AC, Brann MR |title=Identification of a family of muscarinic acetylcholine receptor genes. |journal=Science |volume=237 |issue= 4814 |pages= 527-32 |year= 1987 |pmid= 3037705 |doi= }}
* {{cite journal | vauthors = Badner JA, Yoon SW, Turner G, Bonner TI, Detera-Wadleigh SD | title = Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene. | journal = Mamm. Genome | volume = 6 | issue = 7 | pages = 489–90 | year = 1995 | pmid = 7579899 | doi = 10.1007/BF00360666 }}
*{{cite journal | author=Peralta EG, Ashkenazi A, Winslow JW, ''et al.'' |title=Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. |journal=EMBO J. |volume=6 |issue= 13 |pages= 3923-9 |year= 1988 |pmid= 3443095 |doi=  }}
* {{cite journal | vauthors = Offermanns S, Simon MI | title = G alpha 15 and G alpha 16 couple a wide variety of receptors to phospholipase C. | journal = J. Biol. Chem. | volume = 270 | issue = 25 | pages = 15175–80 | year = 1995 | pmid = 7797501 | doi = 10.1074/jbc.270.25.15175 }}
*{{cite journal | author=Badner JA, Yoon SW, Turner G, ''et al.'' |title=Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene. |journal=Mamm. Genome |volume=6 |issue= 7 |pages= 489-90 |year= 1995 |pmid= 7579899 |doi= }}
* {{cite journal | vauthors = Russell M, Winitz S, Johnson GL | title = Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity. | journal = Mol. Cell. Biol. | volume = 14 | issue = 4 | pages = 2343–51 | year = 1994 | pmid = 8139539 | pmc = 358601 | doi = 10.1128/mcb.14.4.2343 }}
*{{cite journal | author=Offermanns S, Simon MI |title=G alpha 15 and G alpha 16 couple a wide variety of receptors to phospholipase C. |journal=J. Biol. Chem. |volume=270 |issue= 25 |pages= 15175-80 |year= 1995 |pmid= 7797501 |doi= }}
* {{cite journal | vauthors = Kunapuli P, Onorato JJ, Hosey MM, Benovic JL | title = Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5. | journal = J. Biol. Chem. | volume = 269 | issue = 2 | pages = 1099–105 | year = 1994 | pmid = 8288567 | doi =  }}
*{{cite journal | author=Russell M, Winitz S, Johnson GL |title=Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity. |journal=Mol. Cell. Biol. |volume=14 |issue= 4 |pages= 2343-51 |year= 1994 |pmid= 8139539 |doi= }}
* {{cite journal | vauthors = Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H | title = Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C. | journal = J. Biol. Chem. | volume = 271 | issue = 5 | pages = 2776–82 | year = 1996 | pmid = 8576254 | doi = 10.1074/jbc.271.5.2776 }}
*{{cite journal | author=Kunapuli P, Onorato JJ, Hosey MM, Benovic JL |title=Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5. |journal=J. Biol. Chem. |volume=269 |issue= 2 |pages= 1099-105 |year= 1994 |pmid= 8288567 |doi=  }}
* {{cite journal | vauthors = Kostenis E, Conklin BR, Wess J | title = 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. | journal = Biochemistry | volume = 36 | issue = 6 | pages = 1487–95 | year = 1997 | pmid = 9063897 | doi = 10.1021/bi962554d }}
*{{cite journal | author=Haga K, Kameyama K, Haga T, ''et al.'' |title=Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C. |journal=J. Biol. Chem. |volume=271 |issue= 5 |pages= 2776-82 |year= 1996 |pmid= 8576254 |doi= }}
* {{cite journal | vauthors = Smiley JF, Levey AI, Mesulam MM | title = Infracortical interstitial cells concurrently expressing m2-muscarinic receptors, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate-diaphorase in the human and monkey cerebral cortex. | journal = Neuroscience | volume = 84 | issue = 3 | pages = 755–69 | year = 1998 | pmid = 9579781 | doi = 10.1016/S0306-4522(97)00524-1 }}
*{{cite journal | author=Kostenis E, Conklin BR, Wess J |title=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. |journal=Biochemistry |volume=36 |issue= 6 |pages= 1487-95 |year= 1997 |pmid= 9063897 |doi= 10.1021/bi962554d }}
* {{cite journal | vauthors = von der Kammer H, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch RM | title = Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. | journal = J. Biol. Chem. | volume = 273 | issue = 23 | pages = 14538–44 | year = 1998 | pmid = 9603968 | doi = 10.1074/jbc.273.23.14538 }}
*{{cite journal | author=Smiley JF, Levey AI, Mesulam MM |title=Infracortical interstitial cells concurrently expressing m2-muscarinic receptors, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate-diaphorase in the human and monkey cerebral cortex. |journal=Neuroscience |volume=84 |issue= 3 |pages= 755-69 |year= 1998 |pmid= 9579781 |doi= }}
* {{cite journal | vauthors = Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K | title = Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. | journal = Neurosci. Lett. | volume = 266 | issue = 1 | pages = 17–20 | year = 1999 | pmid = 10336173 | doi = 10.1016/S0304-3940(99)00259-1 }}
*{{cite journal | author=von der Kammer H, Mayhaus M, Albrecht C, ''et al.'' |title=Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. |journal=J. Biol. Chem. |volume=273 |issue= 23 |pages= 14538-44 |year= 1998 |pmid= 9603968 |doi= }}
* {{cite journal | vauthors = Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E | title = Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients. | journal = FASEB J. | volume = 13 | issue = 14 | pages = 2015–20 | year = 1999 | pmid = 10544184 | doi =  }}
*{{cite journal | author=Sato KZ, Fujii T, Watanabe Y, ''et al.'' |title=Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. |journal=Neurosci. Lett. |volume=266 |issue= 1 |pages= 17-20 |year= 1999 |pmid= 10336173 |doi= }}
* {{cite journal | vauthors = Waid DK, Chell M, El-Fakahany EE | title = M(2) and M(4) muscarinic receptor subtypes couple to activation of endothelial nitric oxide synthase. | journal = Pharmacology | volume = 61 | issue = 1 | pages = 37–42 | year = 2000 | pmid = 10895079 | doi = 10.1159/000028378 }}
*{{cite journal | author=Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E |title=Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients. |journal=FASEB J. |volume=13 |issue= 14 |pages= 2015-20 |year= 1999 |pmid= 10544184 |doi=  }}
* {{cite journal | vauthors = Obara K, Arai K, Miyajima N, Hatano A, Tomita Y, Takahashi K | title = Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells. | journal = Urol. Res. | volume = 28 | issue = 3 | pages = 196–200 | year = 2000 | pmid = 10929429 | doi = 10.1007/s002400000113 }}
*{{cite journal | author=Waid DK, Chell M, El-Fakahany EE |title=M(2) and M(4) muscarinic receptor subtypes couple to activation of endothelial nitric oxide synthase. |journal=Pharmacology |volume=61 |issue= 1 |pages= 37-42 |year= 2000 |pmid= 10895079 |doi= }}
* {{cite journal | vauthors = Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, Mohr K, De Amici M, Barocelli E, Bertoni S, Dallanoce C | title = Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity. | journal = Eur. J. Med. Chem. | volume = 75 | pages = 222–232 | year = 2014 | pmid = 24534538 | doi = 10.1016/j.ejmech.2014.01.032 }}
*{{cite journal | author=Obara K, Arai K, Miyajima N, ''et al.'' |title=Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells. |journal=Urol. Res. |volume=28 |issue= 3 |pages= 196-200 |year= 2000 |pmid= 10929429 |doi= }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2141 | title = Acetylcholine receptors (muscarinic): M<sub>2</sub> | accessdate = | date = | format = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | archiveurl = | archivedate = | quote = }}
* {{MeshName|CHRM2+protein,+human}}
* {{MeshName|CHRM2+protein,+human}}


{{NLM content}}
{{NLM content}}
{{membrane-protein-stub}}
{{G protein-coupled receptors}}
{{G protein-coupled receptors}}
[[Category:G protein coupled receptors]]
{{Muscarinic acetylcholine receptor modulators}}


[[es:Receptor muscarínico M2]]
{{DEFAULTSORT:Muscarinic Acetylcholine Receptor M2}}
[[Category:Muscarinic acetylcholine receptors]]

Revision as of 00:55, 27 October 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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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]

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 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 no effect on the contractile forces of the ventricular muscle.

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.[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

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

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 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 G beta gamma subunit of the G protein coupled to M2. This part of the G protein can open K+ channels in the parasympathetic notches in the heart, which causes an outward current of potassium, 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

  • methacholine (selective m3 muscarinic agonist)
  • Iper-8-naph (compound 8b, bitopic/dualsteric agonist)[10][11]
  • (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)[12]
  • Berberine

Antagonists

See also

References

  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 Behav. 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". Mol. 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". Behav. Genet. 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". Behav. Genet. 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 (Jul 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". J. Pharmacol. Exp. Ther. 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, W. F & Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. p. 387. ISBN 1-4160-2328-3.
  10. ↑ Matera, Carlo; Flammini, Lisa; Quadri, Marta; Vivo, Valentina; Ballabeni, Vigilio; Holzgrabe, Ulrike; Mohr, Klaus; De Amici, Marco; Barocelli, Elisabetta (2014-03-21). "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.
  11. ↑ Bock, Andreas; Merten, Nicole; Schrage, Ramona; Dallanoce, Clelia; Bätz, Julia; Klöckner, Jessica; Schmitz, Jens; Matera, Carlo; Simon, Katharina (2012-09-04). "The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling". Nature Communications. 3: 1044. doi:10.1038/ncomms2028. ISSN 2041-1723. PMC 3658004. PMID 22948826.
  12. ↑ 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". J. Med. Chem. 49 (6): 1925–31. doi:10.1021/jm0510878. PMID 16539379.
  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". Eur. J. Pharmacol. 144 (2): 117–24. doi:10.1016/0014-2999(87)90509-7. PMID 3436364.

Further reading

  • Goyal RK (1989). "Muscarinic receptor subtypes. Physiology and clinical implications". N. Engl. J. Med. 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". Prog. Brain Res. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. PMID 8248499.
  • van Koppen CJ, Nathanson NM (1991). "Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. Analysis of the role of N-glycosylation in receptor expression and function". J. Biol. Chem. 265 (34): 20887–92. PMID 2249995.
  • Ashkenazi A, Ramachandran J, Capon DJ (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 (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 (1988). "Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors". EMBO J. 6 (13): 3923–9. PMC 553870. PMID 3443095.
  • Badner JA, Yoon SW, Turner G, Bonner TI, Detera-Wadleigh SD (1995). "Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene". Mamm. Genome. 6 (7): 489–90. doi:10.1007/BF00360666. PMID 7579899.
  • Offermanns S, Simon MI (1995). "G alpha 15 and G alpha 16 couple a wide variety of receptors to phospholipase C.". J. Biol. Chem. 270 (25): 15175–80. doi:10.1074/jbc.270.25.15175. PMID 7797501.
  • Russell M, Winitz S, Johnson GL (1994). "Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity". Mol. Cell. Biol. 14 (4): 2343–51. doi:10.1128/mcb.14.4.2343. PMC 358601. PMID 8139539.
  • Kunapuli P, Onorato JJ, Hosey MM, Benovic JL (1994). "Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5". J. Biol. Chem. 269 (2): 1099–105. PMID 8288567.
  • Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H (1996). "Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C.". J. Biol. Chem. 271 (5): 2776–82. doi:10.1074/jbc.271.5.2776. PMID 8576254.
  • Kostenis E, Conklin BR, Wess J (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 (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 (1998). "Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors". J. Biol. Chem. 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 (1999). "Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines". Neurosci. Lett. 266 (1): 17–20. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173.
  • Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E (1999). "Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients". FASEB J. 13 (14): 2015–20. PMID 10544184.
  • Waid DK, Chell M, El-Fakahany EE (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 (2000). "Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells". Urol. Res. 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 (2014). "Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity". Eur. J. Med. Chem. 75: 222–232. doi:10.1016/j.ejmech.2014.01.032. PMID 24534538.

External links

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

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