Википедија

Dopaminski receptor D2

Dopaminski receptor D2 (D2R) je protein koji je kod ljudi kodiran DRD2 genom.

Dopaminski receptor D2
Prikaz baziran na PDB 1I15.
Dostupne strukture
1I15, 2HLB
Identifikatori
Simboli DRD2; D2DR; D2R
Vanjski ID OMIM: 126450 MGI: 94924 HomoloGene: 22561 IUPHAR: D2 GeneCards: DRD2 Gene
Pregled RNK izražavanja
PBB GE DRD2 216924 s at tn.png
PBB GE DRD2 206590 x at tn.png
PBB GE DRD2 211624 s at tn.png
podaci
Ortolozi
Vrsta Čovek Miš
Entrez 1813 13489
Ensembl ENSG00000149295 ENSMUSG00000032259
UniProt P14416 P61168
RefSeq (mRNA) NM_000795.3 NM_010077.2
RefSeq (protein) NP_000786.1 NP_034207.2
Lokacija (UCSC) Chr 11:
113.28 - 113.35 Mb		 Chr 9:
49.15 - 49.22 Mb
PubMed pretraga [1] [2]

FunkcijaУреди

Ovaj gen kodira D2 podtip dopaminskog receptora. Taj G protein spregnuti receptor inhibira aktivnost adenilil ciklaze. Misens mutacija ovog gena uzrokuje mioklonalnu distoniju; druge mutacije su vile vezane za šizofreniju.[1]

Alternativno splajsovanje ovog gena proizvodi dve transkriptne varijante koje kodiraju različite izoforme. Treća varijanta je bila opisana, ali nije određeno da li je ona normalna forma ili je posledica aberantnog splajsovanja.[2]

Kod miševa, regulacija D2R površinskog izražavanja putem kalcijumovog senzora NCS-1 u gyrus dentatus kontroliše sinaptičku plastičnost i formiranje memorije.[3]

GenetikaУреди

Variante alela:

  • A-241G
  • C132T, G423A, T765C, C939T, C957T i G1101A[4]
  • Cys311Ser
  • -141C umetak/brisanje[5] Polimorfizmi su bili istraženi u pogledu asocijacije sa šizofrenijom.[6]

Ranija israživanja su uspostavila asocijaciju između polimorfizma Taq 1A (rs1800497) i DRD2 gena. Međutim, polimorfizam je prisutan u eksonu 8 ANKK1 gena.[7]

LigandiУреди

Većina starijih antipsihotičkih lekova, kao što su hlorpromazin i haloperidol, su antagonisti dopaminskog D2 receptora, ali su generalno veoma neselektivni. Oni su u najboljem slučaju selektivni samo za "D2-sličnu familiju" receptora, tako da se vezuju za D2, D3 i D4, a često i za mnoge druge receptore kao što su serotoninski i histaminski. To proizvodi niz nuspojava i čini ih nepodesnim za naučna istraživanja. Slično tome, stariji dopaminski agonisti koji su korišteni za Parkinsonovu bolest poput bromokriptina i kabergolina su slabo selektivi za pojedinači tip dopaminskog receptora, te mada većina njih deluju kao D2 agonisti, oni utiču i na druge podtipove. Nekoliko selektivnih D2 liganda je dostupno.

AgonistiУреди

AntagonistiУреди

D2Sh selektivni (presinaptički autoreceptori)

InterakcijeУреди

Za dopaminski receptor D2 je pokazano da formira interakcije sa adenozinskim A2A receptorom,[13] EPB41L1,[14] PPP1R9B[15] i NCS-1.[16]

IzvoriУреди

  1. ^ „Gene Overview of All Published Schizophrenia-Association Studies for DRD2”. Schizophrenia Research Forum. 26. 3. 2009. Архивирано из оригинала 21. 02. 2009. г. Приступљено 9. 6. 2009. 
  2. ^ „Entrez Gene: DRD2 dopamine receptor D2”. 
  3. ^ Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC (2009). „NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory.”. Neuron. 63 (5): 643—56. PMID 19755107. doi:10.1016/j.neuron.2009.08.014. 
  4. ^ Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (2003). „Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor”. Hum. Mol. Genet. 12 (3): 205—16. PMID 12554675. doi:10.1093/hmg/ddg055. 
  5. ^ Arinami T, Gao M, Hamaguchi H, Toru M (1997). „A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia”. Hum. Mol. Genet. 6 (4): 577—82. PMID 9097961. doi:10.1093/hmg/6.4.577. 
  6. ^ Glatt SJ; Stephen Faraone; Tsuang MT (2004). „DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis”. Am. J. Med. Genet. B Neuropsychiatr. Genet. 128B (1): 21—3. PMID 15211624. doi:10.1002/ajmg.b.30007. 
  7. ^ Lucht M, Rosskopf D (2008). „Comment on "Genetically determined differences in learning from errors"”. Science. 321 (5886): 200; author reply 200. PMID 18621654. doi:10.1126/science.1155372. 
  8. ^ „Clinical Pharmacology for Abilify”. RxList.com. 21. 1. 2010. Приступљено 21. 1. 2010. 
  9. ^ Holmes IP, Blunt RJ, Lorthioir OE, Blowers SM, Gribble A, Payne AH, Stansfield IG, Wood M, Woollard PM, Reavill C, Howes CM, Micheli F, Di Fabio R, Donati D, Terreni S, Hamprecht D, Arista L, Worby A, Watson SP (2010). „The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure”. Bioorganic & Medicinal Chemistry Letters. 20 (6): 2013—6. PMID 20153647. doi:10.1016/j.bmcl.2010.01.090. 
  10. ^ Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B (1998). „Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro”. Life Sci. 63 (3): 215—22. PMID 9698051. doi:10.1016/S0024-3205(98)00262-8. 
  11. ^ Wang GJ, Volkow ND, Thanos PK, Fowler JS (2004). „Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review”. J Addict Dis. 23 (3): 39—53. PMID 15256343. doi:10.1300/J069v23n03_04. 
  12. ^ Philip Seeman, M.D.; Teresa Tallerico. „Rapid Release of Antipsychotic Drugs From Dopamine D2 Receptors: An Explanation for Low Receptor Occupancy and Early Clinical Relapse Upon Withdrawal of Clozapine or Quetiapine”. The American Journal of Psychiatry. 156 (6). 
  13. ^ Kamiya T, Saitoh O, Yoshioka K, Nakata H (2003). „Oligomerization of adenosine A2A and dopamine D2 receptors in living cells”. Biochem. Biophys. Res. Commun. 306 (2): 544—9. PMID 12804599. doi:10.1016/S0006-291X(03)00991-4. 
  14. ^ Binda AV, Kabbani N, Lin R, Levenson R (2002). „D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N”. Mol. Pharmacol. 62 (3): 507—13. PMID 12181426. doi:10.1124/mol.62.3.507. 
  15. ^ Smith FD, Oxford GS, Milgram SL (1999). „Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein”. J. Biol. Chem. 274 (28): 19894—900. PMID 10391935. doi:10.1074/jbc.274.28.19894. 
  16. ^ Kabbani N, Negyessy L, Lin R, Goldman-Rakic, Levenson R. (2002). „Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor.”. J. Neurosci. 22 (19): 8476—86. PMID 12351722. 

LiteraturaУреди

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Spoljašnje vezeУреди

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