Melanokortinski 4 receptor

Melanokortin 4 receptor
Identifikatori
Simboli	MC4R; MGC126851; MGC138197
Vanjski ID	OMIM: 155541 MGI: 99457 HomoloGene: 4320 IUPHAR: MC4 GeneCards: MC4R Gene
Ontologija gena Molekularna funkcija • rodopsinu-sličan receptorska aktivnost • receptorska aktivnost • aktivnost melanokortin receptora • proteinsko vezivanje Celularna komponenta • membrana plazma • integralno sa membranom Biološki proces • prenos signala • signalni put G-protein spregnutog receptora • G-protein signalizacija, spregnuta sa cAMP nukleotid drugim glasnikom • ishrana • regulacija metaboličkog procesa • pozitivna regulacija resorpcije kosti
Pregled RNK izražavanja
podaci
Ortolozi
Vrsta	Čovek	Miš
Entrez	4160	17202
Ensembl	ENSG00000166603	ENSMUSG00000047259
UniProt	P32245	Q49NR1
RefSeq (mRNA)	NM_005912	NM_016977
RefSeq (protein)	NP_005903	NP_058673
Lokacija (UCSC)	Chr 18: 56.19 - 56.19 Mb	Chr 18: 66.98 - 66.99 Mb
PubMed pretraga	[1]	[2]

Melanokortin receptor 4 je protein koji je kod ljudi kodiran MC4R genom.^[1][2][3] Ova gen kodira MC₄ protein, G-protein spregnuti receptor koji vezuje α-melanocit stimulišući hormon (α-MSH). U modelima na glodarima za MC₄ receptore je bilo ustanovljeno da učestvuju u ishrani, regulaciji metabolizma, seksualnom ponašanju, i muškoj erektilnoj funkciji^[4][5][6]

1998 godine je bilo objavljeno da su MC4R mutacije vezane za naslednu gojaznost kod ljudi. One su nađene kod heterozigota, što sugestira autozomni dominantni nasledni trend. Međutim, na bazi drugih istraživanja i opažanja, te mutacije izgleda da imaju delimičnu penetrantnost i određeni stupanj kodominantnosti. Njihova zastupljenost od 1-2.5% kod ljudi sa BMI većim od 30, čini ih najzastupljenijim među poznatim genetskim defektima koji predispozicioniraju ljude ka gojaznosti.^[7]

Interakcije

Za melanokortin 4 receptor je bilo pokazano da interaguje sa proopiomelanokortinom.^[8][9]

Klinički značaj

2009 godine su sprovedene dve veoma velike BMI asocijacione studije koje su obuhvatale celokupni genom. One su potvrdile asocijaciju varijanti sa oko 150 kilo baza nizvodno od MC4R gena sa otpornošću na insulin, gojažnošću i drugim antropometrijskim odlikama.^{[10][11][12][13]}

Vidi još

• Melanokortin receptor

Reference

1. Magenis RE, Smith L, Nadeau JH, Johnson KR, Mountjoy KG, Cone RD (1994). „Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human”. Mamm Genome. 5 (8): 503—8. PMID 7949735. doi:10.1007/BF00369320. 
2. Sundaramurthy D, Campbell DA, Leek JP, Markham AF, Pieri LF (1998). „Assignment of the melanocortin 4 receptor (MC4R) gene to human chromosome band 18q22 by in situ hybridisation and radiation hybrid mapping”. Cytogenet Cell Genet. 82 (1-2): 97—8. PMID 9763669. doi:10.1159/000015074. 
3. „Entrez Gene: MC4R melanocortin 4 receptor”. 
4. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (1997). „Role of melanocortinergic neurons in feeding and the agouti obesity syndrome”. Nature. 385 (6612): 165—168. PMID 8990120. doi:10.1038/385165a0. 
5. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997). „Targeted disruption of the melanocortin-4 receptor results in obesity in mice”. Cell. 88 (1): 131—141. PMID 9019399. doi:10.1016/S0092-8674(00)81865-6. 
6. Van der Ploeg LH, Martin WJ, Howard AD, Nargund RP, Austin CP, Guan X, Drisko J, Cashen D, Sebhat I, Patchett AA, Figueroa DJ, DiLella AG, Connolly BM, Weinberg DH, Tan CP, Palyha OC, Pong SS, MacNeil T, Rosenblum C, Vongs A, Tang R, Yu H, Sailer AW, Fong TM, Huang C, Tota MR, Chang RS, Stearns R, Tamvakopoulos C, Christ G, Drazen DL, Spar BD, Nelson RJ, MacIntyre DE (2002). „A role for the melanocortin 4 receptor in sexual function”. Proc Natl Acad Sci USA. 99 (17): 11381—11386. PMC 123265 . PMID 12172010. doi:10.1073/pnas.172378699. 
7. Farooqi S, O'Rahilly S (2006). „Genetics of obesity in humans”. Endocrine Reviews. 27 (7): 710—718. PMID 17122358. doi:10.1210/er.2006-0040. 
8. Yang, Y K; Fong T M; et al. (2000). „Molecular determinants of ligand binding to the human melanocortin-4 receptor”. Biochemistry. UNITED STATES. 39 (48): 14900—11. ISSN 0006-2960. PMID 11101306. doi:10.1021/bi001684q. 
9. Yang, Y K; Ollmann M M; et al. (1997). „Effects of recombinant agouti-signaling protein on melanocortin action”. Mol. Endocrinol. UNITED STATES. 11 (3): 274—80. ISSN 0888-8809. PMID 9058374. doi:10.1210/me.11.3.274. 
10. Chambers JC; Elliott P; Zabaneh D; et al. (2008). „Common genetic variation near MC4R is associated with waist circumference and insulin resistance.”. Nat. Genet. 40 (6): 716—18. PMID 18454146. doi:10.1038/ng.156. 
11. Loos RJ; Lindgren CM; Li S; Wheeler E; et al. (2008). „Common variants near MC4R are associated with fat mass, weight and risk of obesity.”. Nat. Genet. 40 (6): 768—75. PMC 2669167 . PMID 18454148. doi:10.1038/ng.140. 
12. Thorleifsson G; Walters GB; Gudbjartsson DF; et al. (2009). „Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.”. Nat. Genet. 41 (1): 18—24. PMID 19079260. doi:10.1038/ng.274. 
13. Willer CJ; Speliotes EK; Loos RJ; et al. (2009). „Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.”. Nat. Genet. 41 (1): 24—34. PMC 2695662 . PMID 19079261. doi:10.1038/ng.287. 

Literatura

• Mountjoy KG; Mortrud MT; Low MJ; et al. (1995). „Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.”. Mol. Endocrinol. 8 (10): 1298—308. PMID 7854347. doi:10.1210/me.8.10.1298. 
• Gantz I; Miwa H; Konda Y; et al. (1993). „Molecular cloning, expression, and gene localization of a fourth melanocortin receptor.”. J. Biol. Chem. 268 (20): 15174—9. PMID 8392067. 
• Alvaro JD; Tatro JB; Quillan JM; et al. (1996). „Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction.”. Mol. Pharmacol. 50 (3): 583—91. PMID 8794897. 
• Yang YK; Ollmann MM; Wilson BD; et al. (1997). „Effects of recombinant agouti-signaling protein on melanocortin action.”. Mol. Endocrinol. 11 (3): 274—80. PMID 9058374. doi:10.1210/me.11.3.274. 
• Chagnon YC; Chen WJ; Pérusse L; et al. (1998). „Linkage and association studies between the melanocortin receptors 4 and 5 genes and obesity-related phenotypes in the Québec Family Study.”. Mol. Med. 3 (10): 663—73. PMC 2230227 . PMID 9392003. 
• Yeo GS; Farooqi IS; Aminian S; et al. (1998). „A frameshift mutation in MC4R associated with dominantly inherited human obesity.”. Nat. Genet. 20 (2): 111—2. PMID 9771698. doi:10.1038/2404. 
• Vaisse C, Clement K, Guy-Grand B, Froguel P (1998). „A frameshift mutation in human MC4R is associated with a dominant form of obesity.”. Nat. Genet. 20 (2): 113—4. PMID 9771699. doi:10.1038/2407. 
• Hinney A; Schmidt A; Nottebom K; et al. (1999). „Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans.”. J. Clin. Endocrinol. Metab. 84 (4): 1483—6. PMID 10199800. doi:10.1210/jc.84.4.1483. 
• Yang YK; Dickinson CJ; Zeng Q; et al. (1999). „Contribution of melanocortin receptor exoloops to Agouti-related protein binding.”. J. Biol. Chem. 274 (20): 14100—6. PMID 10318826. doi:10.1074/jbc.274.20.14100. 
• Ho G, MacKenzie RG (2000). „Functional characterization of mutations in melanocortin-4 receptor associated with human obesity.”. J. Biol. Chem. 274 (50): 35816—22. PMID 10585465. doi:10.1074/jbc.274.50.35816. 
• Yang YK; Fong TM; Dickinson CJ; et al. (2001). „Molecular determinants of ligand binding to the human melanocortin-4 receptor.”. Biochemistry. 39 (48): 14900—11. PMID 11101306. doi:10.1021/bi001684q. 
• Mergen M; Mergen H; Ozata M; et al. (2001). „A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity.”. J. Clin. Endocrinol. Metab. 86 (7): 3448. PMID 11443223. doi:10.1210/jc.86.7.3448. 
• McNulty JC; Thompson DA; Bolin KA; et al. (2002). „High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein.”. Biochemistry. 40 (51): 15520—7. PMID 11747427. doi:10.1021/bi0117192. 
• Brocke KS; Neu-Yilik G; Gehring NH; et al. (2002). „The human intronless melanocortin 4-receptor gene is NMD insensitive.”. Hum. Mol. Genet. 11 (3): 331—5. PMID 11823452. doi:10.1093/hmg/11.3.331. 
• Yang Y; Chen M; Lai Y; et al. (2002). „Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity.”. J. Biol. Chem. 277 (23): 20328—35. PMID 11912210. doi:10.1074/jbc.M201343200. 
• Hansen MJ, Morris MJ (2002). „Evidence for an interaction between neuropeptide Y and the melanocortin-4 receptor on feeding in the rat.”. Neuropharmacology. 42 (6): 792—7. PMID 12015205. doi:10.1016/S0028-3908(02)00025-4. 
• Miraglia Del Giudice E; Cirillo G; Nigro V; et al. (2002). „Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity.”. Int. J. Obes. Relat. Metab. Disord. 26 (5): 647—51. PMID 12032748. doi:10.1038/sj.ijo.0801983. 
• Kim CS; Lee SH; Kim RY; et al. (2002). „Identification of domains directing specificity of coupling to G-proteins for the melanocortin MC3 and MC4 receptors.”. J. Biol. Chem. 277 (35): 31310—7. PMID 12045190. doi:10.1074/jbc.M112085200. 
• „Melanocortin Receptors: MC₄”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Архивирано из оригинала 03. 03. 2016. г.