Dopaminski receptor D2

Dopaminski receptor D2
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
Ontologija gena
Molekularna funkcija	• aktivnost dopaminskog receptora, spregnutog preko Gi/Go; • aktivnost dopaminskog receptora, spregnutog preko Gi/Go; • aktivnost signalnog prenosnika; • receptorska aktivnost; • aktivnost G-protein spregnutog receptora; • vezivanje receptora; • proteinsko vezivanje; • vezivanje leka; • aktivnost regulatora kalijum kanala; • dopaminsko vezivanje; • vezivanje jonotropnog glutamatnog receptor;
Celularna komponenta	• akrozomalna vezikula; • rastvorna frakcija; • ćelijska membrana; • integralno sa ćelijskom membranom; • postsinaptička gustina; • integralno sa membranom; • lateralna ćelijska membrana; • flagela; • endocitna vezikula; • akson; • dendrit; • sinaptička membranska vezikula; • citoplazmatična vezikula; • dendritska osnova; • perikarion; • aksonski terminus;
Biološki proces	• homeostaza temperature; • respons na hipoksiju; • sinaptička transmisija, dopaminergička; • respons na amfetamin; • neurološki sistemski proces koji učestvuje u regulaciji sistemičkog arterijskog krvnog pritiska; • regulacija brzine srca; • regulation of sodium ion transport; • regulation of sodium ion transport; • internalizacija G-protein spregnutog receptora; • pozitivna regulacija neuroblastne proliferacije; • pozitivna regulacija receptorske internalizacije; • jonska homeostaza celularnog kalcijuma;
Pregled RNK izražavanja
	podaci
Ortolozi
Vrsta	Čovek
Entrez	1813
Ensembl	ENSG00000149295
UniProt	P14416
RefSeq (mRNA)	NM_000795.3
RefSeq (protein)	NP_000786.1
Lokacija (UCSC)	Chr 11:; 113.28 - 113.35 Mb
PubMed pretraga	[1]

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

Funkcija

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]

Genetika

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]

Ligandi

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.

Agonisti

Aplindor - parcijalni agonist
Aripiprazol - parcijalni agonist^[8]
Brekspiprazol/OPC-34712 - parcijalni agonist
GSK-789,472 - mišoviti D₂ parcijalni agonist / D₃ antagonist, sa dobrom selektivnošću^[9]
Talipeksol - selektivan za D₂ u odnosu na druge dopaminske receptore, ali deluje kao α₂-adrenoceptorski agonist i 5HT₃ antagonist.
OSU-6162 - D₂ parcijalni agonist i 5-HT_2A parcijalni agonist, deluje kao „dopaminski stabilizator“
Piribedil - takođe agonist D3 receptora i α₂-adrenergički antagonist
LSD - in vitro, za LSD je utvrđeno da je parcijalni agonist i da uvećava dopaminom posredovanu sekreciju prolaktina u laktotrofima.^[10] LSD je isto tako 5HT_2A agonist.
Pramipeksol - isto tako agonist D3, D4 receptora
Hinpirol - isto tako agonist D3 receptora
Hineloran
Salvinorin A - parcijalni agonist, takođe agonist k-opioida.
Bromokriptin
Ropinirol

Antagonisti

L-741,626 (3-[4-(4-hlorofenil)-4-hidroksipiperidin-l-il]metil-1H-indol) - visoko selektivan D₂ antagonist
Melperon - D₂ antagonist, ali i 5HT_2A antagonist
Risperidon - D₂ antagonist, ali i 5HT_2A antagonist
Ziprasidon - D₂ antagonist, ali i 5HT_2A antagonist
Rakloprid - Radio obeležen C¹¹rakloprid se često koristi u studijama s primenom pozitronske emisione tomografije^[11]
Klozapin
Haloperidol
Kvetiapin^[12]
Domperidon - D₂ i D₃ antagonist
Etikloprid

D₂Sh selektivni (presinaptički autoreceptori)

Amisulprid (niske doze)
UH-232

Interakcije

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

Izvori

^ „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.
^ „Entrez Gene: DRD2 dopamine receptor D2”.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ „Clinical Pharmacology for Abilify”. RxList.com. 21. 1. 2010. Приступљено 21. 1. 2010.
^ 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.
^ 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.
^ 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.
^ 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). Архивирано из оригинала 23. 10. 2010. г. Приступљено 12. 03. 2012.
^ 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.
^ 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.
^ 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.
^ 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.

Literatura

Missale C; Nash SR; Robinson SW; et al. (1998). „Dopamine receptors: from structure to function”. Physiol. Rev. 78 (1): 189—225. PMID 9457173.
Sidhu A, Niznik HB (2000). „Coupling of dopamine receptor subtypes to multiple and diverse G proteins”. Int. J. Dev. Neurosci. 18 (7): 669—77. PMID 10978845. doi:10.1016/S0736-5748(00)00033-2.
Araki K; Kuwano R; Morii K; et al. (1993). „Structure and expression of human and rat D2 dopamine receptor genes”. Neurochem. Int. 21 (1): 91—8. PMID 1363862. doi:10.1016/0197-0186(92)90071-X.
Eubanks JH; Djabali M; Selleri L; et al. (1993). „Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11q23”. Genomics. 14 (4): 1010—8. PMID 1478642. doi:10.1016/S0888-7543(05)80124-7.
Dearry A, Falardeau P, Shores C, Caron MG (1992). „D2 dopamine receptors in the human retina: cloning of cDNA and localization of mRNA”. Cell. Mol. Neurobiol. 11 (5): 437—53. PMID 1835903. doi:10.1007/BF00734808.
Sarkar G; Kapelner S; Grandy DK; et al. (1992). „Direct sequencing of the dopamine D2 receptor (DRD2) in schizophrenics reveals three polymorphisms but no structural change in the receptor”. Genomics. 11 (1): 8—14. PMID 1837284. doi:10.1016/0888-7543(91)90096-W.
Stormann TM, Gdula DC, Weiner DM, Brann MR (1990). „Molecular cloning and expression of a dopamine D2 receptor from human retina”. Mol. Pharmacol. 37 (1): 1—6. PMID 2137193.
Robakis NK; Mohamadi M; Fu DY; et al. (1990). „Human retina D2 receptor cDNAs have multiple polyadenylation sites and differ from a pituitary clone at the 5' non-coding region”. Nucleic Acids Res. 18 (5): 1299. PMC 330461  . PMID 2138729. doi:10.1093/nar/18.5.1299.
Selbie LA, Hayes G, Shine J (1990). „DNA homology screening: isolation and characterization of the human D2A dopamine receptor subtype”. Adv. Second Messenger Phosphoprotein Res. 24: 9—14. PMID 2144985.
Monsma FJ; McVittie LD; Gerfen CR; et al. (1990). „Multiple D2 dopamine receptors produced by alternative RNA splicing”. Nature. 342 (6252): 926—9. PMID 2480527. doi:10.1038/342926a0.
Dal Toso R; Sommer B; Ewert M; et al. (1990). „The dopamine D2 receptor: two molecular forms generated by alternative splicing”. EMBO J. 8 (13): 4025—34. PMC 401577  . PMID 2531656.
Grandy DK; Marchionni MA; Makam H; et al. (1990). „Cloning of the cDNA and gene for a human D2 dopamine receptor”. Proc. Natl. Acad. Sci. U.S.A. 86 (24): 9762—6. PMC 298581  . PMID 2532362. doi:10.1073/pnas.86.24.9762.
Selbie LA, Hayes G, Shine J (1990). „The major dopamine D2 receptor: molecular analysis of the human D2A subtype”. DNA. 8 (9): 683—9. PMID 2533064.
Leysen JE; Gommeren W; Mertens J; et al. (1995). „Comparison of in vitro binding properties of a series of dopamine antagonists and agonists for cloned human dopamine D2S and D2L receptors and for D2 receptors in rat striatal and mesolimbic tissues, using [125I] 2'-iodospiperone”. Psychopharmacology (Berl.). 110 (1–2): 27—36. PMID 7870895. doi:10.1007/BF02246947.
Itokawa M; Arinami T; Futamura N; et al. (1994). „A structural polymorphism of human dopamine D2 receptor, D2(Ser311-->Cys)”. Biochem. Biophys. Res. Commun. 196 (3): 1369—75. PMID 7902708. doi:10.1006/bbrc.1993.2404.
Malmberg A, Jackson DM, Eriksson A, Mohell N (1993). „Unique binding characteristics of antipsychotic agents interacting with human dopamine D2A, D2B, and D3 receptors”. Mol. Pharmacol. 43 (5): 749—54. PMID 8099194.
Seeman P; Ohara K; Ulpian C; et al. (1993). „Schizophrenia: normal sequence in the dopamine D2 receptor region that couples to G-proteins. DNA polymorphisms in D2”. Neuropsychopharmacology. 8 (2): 137—42. PMID 8471125.
Cravchik A, Sibley DR, Gejman PV (1996). „Functional analysis of the human D2 dopamine receptor missense variants”. J. Biol. Chem. 271 (42): 26013—7. PMID 8824240. doi:10.1074/jbc.271.42.26013.
Ho MK, Wong YH (1997). „Functional role of amino-terminal serine16 and serine27 of G alphaZ in receptor and effector coupling”. J. Neurochem. 68 (6): 2514—22. PMID 9166747. doi:10.1046/j.1471-4159.1997.68062514.x.
Centonze D; Gubellini P; et al. (2004). „Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum”. Neuroscience. 129 (1): 157—66. PMID 15489038. doi:10.1016/j.neuroscience.2004.07.043.

Vidi još

Dopaminski receptor

Spoljašnje veze

Receptors,+Dopamine+D2 на US National Library of Medicine Medical Subject Headings (MeSH)
Pappas, Stephanie. „Study: Genes Influence Who Your Friends Are”. Imaginova Corp. LiveScience. Приступљено 20. 1. 2011.

[Schizophrenia_Research_Forum-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.

[entrez-2] „Entrez Gene: DRD2 dopamine receptor D2”.

[pmid19755107-3] 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.

[pmid12554675-4] 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.

[pmid9097961-5] 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.

[pmid15211624-6] 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.

[pmid18621654-7] 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.

[Rxlist_-_Abilify-8] „Clinical Pharmacology for Abilify”. RxList.com. 21. 1. 2010. Приступљено 21. 1. 2010.

[pmid20153647-9] 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.

[pmid9698051-10] 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.

[pmid15256343-11] 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). Архивирано из оригинала 23. 10. 2010. г. Приступљено 12. 03. 2012.

[pmid12804599-13] 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.

[pmid12181426-14] 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.

[pmid10391935-15] 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.

[pmid12351722-16] 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.

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