Muscarinic acetylcholine receptor M2

Cholinergic receptor, muscarinic 2
Identifiers
Symbols	CHRM2; FLJ43243; HM2; MGC120006; MGC120007
External IDs	OMIM: 118493 MGI: 88397 HomoloGene: 20190 IUPHAR: M2 GeneCards: CHRM2 Gene
Gene Ontology Molecular function • receptor activity • G-protein coupled receptor activity • muscarinic acetylcholine receptor activity • protein binding Cellular component • plasma membrane • plasma membrane • plasma membrane • integral to plasma membrane • cell junction • synapse • postsynaptic membrane Biological process • G-protein coupled receptor protein signaling pathway • G-protein signaling, coupled to cyclic nucleotide second messenger • G-protein signaling, coupled to cAMP nucleotide second messenger • activation of phospholipase C activity by muscarinic acetylcholine receptor signaling pathway • nervous system development • regulation of heart contraction • response to virus Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1129	243764
Ensembl	ENSG00000181072	ENSMUSG00000045613
UniProt	P08172	Q05CZ8
RefSeq (mRNA)	NM_000739.2	NM_203491.3
RefSeq (protein)	NP_000730.1	NP_987076.2
Location (UCSC)	Chr 7: 136.55 – 136.71 Mb	Chr 6: 36.34 – 36.48 Mb
PubMed search	[1]	[2]

The muscarinic acetylcholine receptor M₂, 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 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 2006 Dutch family study found that there is "a highly significant association" between the CHRM2 gene and intelligence. The study concluded that there was an association between the CHRM2 gene on chromosome 7 and Performance IQ, as measured by the Wechsler Adult Intelligence Scale-Revised. The Dutch family study used a sample of 667 individuals from 304 families.^[1] A similar association was found independently in the Minnesota Twin and Family Study (Comings et al. 2003) and by the Department of Psychiatry at the Washington University.^[2] However, a larger 2009 study attempting to replicate this claim instead found no significant association between the CHRM2 gene and intelligence in a Scottish cohort of 2,091 individuals over age 50, nor an English sample of 758 non-cognitively-impaired elderly individuals, nor an Australian family-based sample of 1,537 adolescents.^[3]

Mechanism

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.

In addition, they modulate muscarinic potassium channels.^[4][5] In the heart, this contributes to a decreased heart rate.

Gene

Muscarinic acetylcholine receptor M2 is encoded by the gene CHRM2.^[6]

Multiple alternatively spliced transcript variants have been described for this gene.^[6]

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

• Bethanechol (nonselective muscarinic agonist)
• (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)^[7]

Antagonists

• Dimethindene - N,N-Dimethyl-3-[(1S)-1-(2-pyridinyl)ethyl]-1H-indene-2-ethanamine, CAS# 121367-05-3, mixed M2 / histamine H1 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

See also

• Muscarinic acetylcholine receptor

References

1. ^ Gosso MF, van Belzen M, de Geus EJ, et al. (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. 
2. ^ Dick DM, Aliev F, Kramer J, et al. (2007). "Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence". Behav. Genet. 37 (2): 265–272. doi:10.1007/s10519-006-9131-2. PMID 17160701. 
3. ^ Lind PA, Luciano M, Horan MA, et al. (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. 
4. ^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. 
5. ^ Boron, W. F and Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. pp. 387. ISBN 1-4160-2328-3. 
6. ^ ^{a b} "Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1129. 
7. ^ 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. 

Further reading

• Goyal RK; Underhill, Lisa H.; Goyal, Raj K. (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, et al. (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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=553870. 
• Badner JA, Yoon SW, Turner G, et al. (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. PMC 358601. PMID 8139539. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=358601. 
• 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, et al. (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, et al. (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, et al. (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, et al. (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. 

External links

• "Acetylcholine receptors (muscarinic): M₂". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2141. 

• MeSH CHRM2+protein,+human

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

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