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Muskarinski acetilholinski receptor M2‎‎
Muskarinski acetilholinski receptor M2‎‎
Identifikatori
Simboli	CHRM2; FLJ43243; HM2; MGC120006; MGC120007
Vanjski ID	OMIM: 118493 MGI: 88397 HomoloGene: 20190 IUPHAR: M2 GeneCards: CHRM2 Gene
Ontologija gena
Molekularna funkcija	• aktivnost receptora; • aktivnost G-protein spregnutog receptora; • aktivnost muskarinskog acetilholinskog receptora; • proteinsko vezivanje;
Celularna komponenta	• ćelijska membrana; • integralno sa ćelijskom membranom; • sinapse; • postsinaptička membrana;
Biološki proces	• signalni put G-protein spregnutog receptora; • G-proteinska signalizacija, spregnuta sa cikličnim nukleotidnim drugim glasnikom; • G-proteinska signalizacija, spregnuta sa cAMP nucleotidnim drugim glasnikom; • aktivacija aktivnosti fosfolipaze C signalnim putem muskarinskog acetilholinskog receptora; • razvoj nervnog sistema; • regulacija kontrakcija srca; • respons na virus;
Ortolozi
Vrsta	Čovek
Entrez	1129
Ensembl	ENSG00000181072
UniProt	P08172
RefSeq (mRNA)	NM_000739.2
RefSeq (protein)	NP_000730.1
Lokacija (UCSC)	Chr 7:; 136.55 - 136.71 Mb
PubMed pretraga	[1]

Muskarinski acetilholinski receptor M₂ (holinergički receptor, muskarinski 2) je muskarinski acetilholinski receptor.

Funkcija

Srce

M2 muskarinski receptori su locirani u srcu, gde usporavaju brzinu srca do normalnog sinusnog ritma nakon stimulatornog dejstva simpatetičkog nervnog sistema, putem usporavanja brzine depolarizacije. Oni takođe redukuju kontraktilne sile atrijalnog srčanog mišića, i umanjuju provodnu brzinu atrioventrikularnog čvora (AV čvor). Oni nemaju efekta na kontrakcione sile ventrikularnog mišića.

IQ

Jedna danska porodična studija iz 2006 je utvrdila da postoji "veoma značajna veze" između CHRM2 gena i inteligencije. Ova studija je koristila uzorak od 667 osoba iz 304 porodice.^[1] Slična veza je nezavisno nađena u studiji blizanaca i porodica u Minesoti.^[2] Međutim, kasniji pokušaji iz 2009. da se potvrde ove tvrdnje je bili neuspešni.^[3]

Mehanizam

M2 muskarinski receptori deluju putem G_i tipa receptora, koji uzrokuju smanjenje cAMP koncentracije u ćeliji, generalno dovodeći do inhibitornih efekata.

Oni takođe moduliraju muskarinske kalijumove kanale.^[4]^[5] U srcu, oni doprinose smanjenju brzine rada srca.

Gen

Muskarinski acetilholinski receptor M2 je kodiran genom CHRM2.^[6] Višestruke alternativno splajsovane transkriptne varijante ovog gene au nađene.^[6]

Ligandi

Nekoliko visoko selektivnih M2 agonista je trenutno dostupno. Brojni neselektivni agonisti i antagonisti su poznati.

Agonisti

Betanehol (neselektivni muskarinski agonist)
(2S,2'R,3'S,5'R)-1-methil-2-(2-methil-1,3-oksatiolan-5-il)pirolidin 3-sulfokside metil jodid (selektivni parcijalni M2 agonist)^[7]

Antagonisti

Dimetinden - N,N-Dimetil-3-[(1S)-1-(2-piridinil)etil]-1H-inden-2-etanamin, CAS# 121367-05-3, mešoviti M2 / histamin H1 antagonist
Otenzepad - 11-([2-[(Dietilamino)metil]-1-piperidinil]acetil)-5,11-dihidro-6H-pirido[2,3-b][1,4]benzodiazepin-6-on, CAS# 102394-31-0
AQRA-741 - 11-([4-[4-(Dietilamino)butil]-1-piperidinil]acetil)-5,11-dihidro-6H-pirido[2,3-b][1,4]benzodiazepin-6-on, CAS# 123548-16-3
AFDX-384 (mešoviti M2/M4 antagonist) - N-[2-[2-[(Dipropilamino)metil]-1-piperidinil]etil]-5,6-dihidro-6-okso-11H-pirido[2,3-b][1,4]benzodiazepin-11-karboksamid, CAS# 118290-27-0

Vidi još

Muskarinski acetilholinski receptor

Reference

^ 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. PMID 17081262. doi:10.1111/j.1601-183X.2006.00211.x.
^ 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. PMID 17160701. doi:10.1007/s10519-006-9131-2.
^ Lind, PA; Luciano M; Horan, MA; et al. (2009). „No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples”. Behav. Genet. 39 (5): 513—23. PMID 19418213. doi:10.1007/s10519-009-9274-z.
^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4.
^ Boron, W. F & Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. стр. 387. ISBN 978-1-4160-2328-9.
^ ^а ^б „Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2”.
^ 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 (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. PMID 16539379. doi:10.1021/jm0510878.

Literatura

Goyal, RK; Underhill, Lisa H.; Goyal, Raj K. (1989). „Muscarinic receptor subtypes. Physiology and clinical implications.”. N. Engl. J. Med. 321 (15): 1022—9. PMID 2674717. doi:10.1056/NEJM198910123211506.
Brann, MR; Ellis J; Jørgensen H; et al. (1994). „Muscarinic acetylcholine receptor subtypes: localization and structure/function.”. Prog. Brain Res. 98: 121—7. PMID 8248499. doi:10.1016/S0079-6123(08)62388-2.
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. PMID 2739737. doi:10.1038/340146a0.
Bonner TI, Buckley NJ, Young AC, Brann MR (1987). „Identification of a family of muscarinic acetylcholine receptor genes.”. Science. 237 (4814): 527—32. PMID 3037705. doi:10.1126/science.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.
Badner, JA; SW, Yoon; Turner G; et al. (1995). „Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene.”. Mamm. Genome. 6 (7): 489—90. PMID 7579899. doi:10.1007/BF00360666.
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. PMID 7797501. doi:10.1074/jbc.270.25.15175.
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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. PMID 8576254. doi:10.1074/jbc.271.5.2776.
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. PMID 9063897. doi:10.1021/bi962554d.
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. PMID 9579781. doi:10.1016/S0306-4522(97)00524-1.
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. PMID 9603968. doi:10.1074/jbc.273.23.14538.
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. PMID 10336173. doi:10.1016/S0304-3940(99)00259-1.
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. PMID 10895079. doi:10.1159/000028378.
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. PMID 10929429. doi:10.1007/s002400000113.
Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4.
Boron, W. F & Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. стр. 387. ISBN 978-1-4160-2328-9.

Spoljašnje veze

„Acetylcholine receptors (muscarinic): M₂”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Архивирано из оригинала 02. 01. 2015. г.
CHRM2+protein,+human на US National Library of Medicine Medical Subject Headings (MeSH)

[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. PMID 17081262. doi:10.1111/j.1601-183X.2006.00211.x.

[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. PMID 17160701. doi:10.1007/s10519-006-9131-2.

[3] Lind, PA; Luciano M; Horan, MA; et al. (2009). „No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples”. Behav. Genet. 39 (5): 513—23. PMID 19418213. doi:10.1007/s10519-009-9274-z.

[Rang-4] Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4.

[Boron-5] Boron, W. F & Boulpaep, E. L. (2005). Medical Physiology. Philadelphia: Elsevier Saunders. стр. 387. ISBN 978-1-4160-2328-9.

[entrez-6] а ^б „Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2”.

[pmid16539379-7] 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 (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. PMID 16539379. doi:10.1021/jm0510878.

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