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多巴胺受體D2

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DRD2
Protein DRD2 PDB 1I15.png
已知的結構
PDBOrtholog search: PDBe RCSB
識別號
别名DRD2;D2DR、​D2R、​dopamine receptor D2
外部IDOMIM126450 MGI94924 HomoloGene22561 GeneCardsDRD2
為以下藥物的標靶
benzquinamide、​LP-12、​LP-211、​LP-44、​力必平、​羅替戈汀、​维拉佐酮、​7-hydroxy-2-(di-N-propylamino)tetralin、​溴隱亭、​多巴胺、​培高利特、​普拉克索、​quinelorane、​quinpirole、​sumanirole、​阿樸嗎啡、​阿立哌唑、​brexpiprazole、​過乳降、​麥角乙脲、​吡貝地爾、​roxindole、​terguride、​氨磺必利、​布南色林、​(+)-butaclamol、​氯丙嗪、​氯氮平、​多潘立酮、​eticlopride、​(Z)-flupentixol、​氟奋乃静、​氟哌啶醇、​L-741,626、​loxapine、​mesoridazine、​nafadotride、​奥氮平、​perospirone、​perphenazine、​匹莫齊特、​pipotiazine、​普樂明、​promazine、​喹硫平、​raclopride、​維思通、​sertindole、​舒必利、​levosulpiride、​trifluoperazine、​齊拉西酮、​zotepine[1]
RNA表达模式
PBB GE DRD2 206590 x at fs.png

PBB GE DRD2 216924 s at fs.png

PBB GE DRD2 211624 s at fs.png
更多參考(基因)表达數據
直系同源
物種人類小鼠
Entrez
Ensembl
UniProt
mRNA​序列

NM_016574、NM_000795、XM_017017296

NM_010077、XM_006509996

蛋白序列

NP_000786、NP_057658、XP_016872785
NP_000786.1

NP_034207、XP_006510059

基因位置​(UCSC)Chr 11: 113.41 – 113.48 Mbn/a
PubMed​查找[2][3]
維基數據
檢視/編輯 人類檢視/編輯 小鼠

多巴胺受體D2Dopamine receptor D2,簡稱D2R),為轉譯DRD2 基因的一種多巴胺受體蛋白。D2R最早於1975年為Philip Seeman英语Philip Seeman所發現,並將其命名為「抗精神疾患性多巴胺受體」(antipsychotic dopamine receptor[4]。D2R為所有抗精神病药物的作用標的。

功能[编辑]

D2R屬於一種多巴胺受體英语dopamine receptor,並會與Gi結合。GiG蛋白偶联受体的一種亞型,會抑制腺苷酸环化酶的活性[5]

在小鼠模式中,齒狀回英语dentate gyrusneuronal calcium sensor-1英语neuronal calcium sensor-1(NCS-1)會影響D2R在細胞膜的表現量。這項機制會影響突触可塑性及記憶形成[6]

在蒼蠅模式中,多巴胺性神經元上的D2R自體受器英语autoreceptor能避免神經元死亡,進而引發類帕金森氏症的症狀[7]

同型體[编辑]

Alternative splicing of this gene results in three transcript variants encoding different isoform英语isoforms.[8]

The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[9]The short form (D2Sh) is pre-synaptic and functions as an autoreceptor英语autoreceptor that regulates the levels of dopamine in the synaptic cleft.[9]Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic英语dopaminergic release.[9]A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[10]

基因組[编辑]

等位基因變異:

Some researchers have previously associated the polymorphism Taq 1A (rs1800497) to the DRD2 gene. However, the polymorphism resides in exon 8 of the ANKK1英语ANKK1 gene.[14]DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.[15][16]

配體[编辑]

Most of the older antipsychotic drugs such as chlorpromazine and haloperidol are antagonists for the dopamine D2 receptor, but are, in general, very unselective, at best selective only for the "D2-like family" receptors and so binding to D2, D3 and D4, and often also to many other receptors such as those for serotonin and histamine, resulting in a range of side-effects and making them poor agents for scientific research. In similar manner, older dopamine agonists used for Parkinson's disease such as bromocriptine and cabergoline英语cabergoline are poorly selective for one dopamine receptor over another, and, although most of these agents do act as D2 agonists, they affect other subtypes as well. Several selective D2 ligands are, however, now available, and this number is likely to increase as further research progresses.

受體致活劑[编辑]

部分受體致活劑[编辑]

受體拮抗劑[编辑]

D2sh selective (presynaptic autoreceptors)

異位調控因子[编辑]

Functionally selective ligands[编辑]

  • 參見參考文獻[27]

Protein–protein interactions[编辑]

The dopamine receptor D2 has been shown to interact with EPB41L1英语EPB41L1,[28]PPP1R9B英语PPP1R9B[29]and NCS-1英语NCS-1.[30]

Receptor oligomers[编辑]

The D2 receptor forms receptor heterodimers英语GPCR oligomer in vivo (in living animals) with other G protein-coupled receptors; these include:[31]

The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3英语Dopamine D3 receptor,[34]DRD5英语Dopamine receptor D5,[35]and 5-HT2A英语5-HT2A receptor.[36]

註釋[编辑]

  1. ^ D2sh–TAAR1 is a presynaptic heterodimer which involves the relocation of TAAR1 from the intracellular space to D2sh at the plasma membrane, increased D2sh agonist binding affinity, and signal transduction through the calcium–PKCNFAT英语NFAT pathway and G-protein independent PKBGSK3英语GSK3 pathway.[32][33]

參考文獻[编辑]

  1. ^ 對Dopamine receptor D2起作用的藥物;在維基數據上查看/編輯參考. 
  2. ^ Human PubMed Reference:. 
  3. ^ Mouse PubMed Reference:. 
  4. ^ Madras BK. History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia. Journal of the History of the Neurosciences. 2013, 22 (1): 62–78. PMID 23323533. doi:10.1080/0964704X.2012.678199. 
  5. ^ Usiello A, Baik JH, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E. Distinct functions of the two isoforms of dopamine D2 receptors. Nature. Nov 2000, 408 (6809): 199–203. PMID 11089973. doi:10.1038/35041572. 
  6. ^ Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC. NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory. Neuron. Sep 2009, 63 (5): 643–56. PMID 19755107. doi:10.1016/j.neuron.2009.08.014. 
  7. ^ Wiemerslage L, Schultz BJ, Ganguly A, Lee D. Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture. Journal of Neurochemistry. Aug 2013, 126 (4): 529–40. PMID 23452092. doi:10.1111/jnc.12228. 
  8. ^ Entrez Gene: DRD2 dopamine receptor D2. 
  9. ^ 9.0 9.1 9.2 Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological Reviews. Mar 2011, 63 (1): 182–217. PMID 21303898. doi:10.1124/pr.110.002642. 
  10. ^ UniProt P14416
  11. ^ Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Human Molecular Genetics. Feb 2003, 12 (3): 205–16. PMID 12554675. doi:10.1093/hmg/ddg055. 
  12. ^ Arinami T, Gao M, Hamaguchi H, Toru M. A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Human Molecular Genetics. Apr 1997, 6 (4): 577–82. PMID 9097961. doi:10.1093/hmg/6.4.577. 
  13. ^ Glatt SJ, Faraone SV, Tsuang MT. DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. Jul 2004, 128B (1): 21–3. PMID 15211624. doi:10.1002/ajmg.b.30007. 
  14. ^ Lucht M, Rosskopf D. Comment on "Genetically determined differences in learning from errors". Science. Jul 2008, 321 (5886): 200; author reply 200. PMID 18621654. doi:10.1126/science.1155372. 
  15. ^ Wang J, Liu ZL, Chen B. Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD. Neurology. Jun 2001, 56 (12): 1757–9. PMID 11425949. doi:10.1212/WNL.56.12.1757. 
  16. ^ Wang J, Zhao C, Chen B, Liu ZL. Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease. Neuroscience Letters. Jan 2004, 355 (3): 193–6. PMID 14732464. doi:10.1016/j.neulet.2003.11.006. 
  17. ^ Clinical Pharmacology for Abilify. RxList.com. 2010-01-21 [2010-01-21]. 
  18. ^ 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. The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure. Bioorganic & Medicinal Chemistry Letters. Mar 2010, 20 (6): 2013–6. PMID 20153647. doi:10.1016/j.bmcl.2010.01.090. 
  19. ^ Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B. Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro. Life Sciences. 1998, 63 (3): 215–22. PMID 9698051. doi:10.1016/S0024-3205(98)00262-8. 
  20. ^ Wang GJ, Volkow ND, Thanos PK, Fowler JS. Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review. Journal of Addictive Diseases. 2004, 23 (3): 39–53. PMID 15256343. doi:10.1300/J069v23n03_04. 
  21. ^ Huang R, Griffin SA, Taylor M, Vangveravong S, Mach RH, Dillon GH, Luedtke RR. The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition. Pharmacology. 2013, 92 (1–2): 84–9. PMID 23942137. doi:10.1159/000351971. 
  22. ^ Agnati LF, Ferré S, Genedani S, Leo G, Guidolin D, Filaferro M, Carriba P, Casadó V, Lluis C, Franco R, Woods AS, Fuxe K. Allosteric modulation of dopamine D2 receptors by homocysteine. Journal of Proteome Research. Nov 2006, 5 (11): 3077–83. PMID 17081059. doi:10.1021/pr0601382. 
  23. ^ Beyaert MG, Daya RP, Dyck BA, Johnson RL, Mishra RK. PAOPA, a potent dopamine D2 receptor allosteric modulator, prevents and reverses behavioral and biochemical abnormalities in an amphetamine–sensitized preclinical animal model of schizophrenia. European Neuropsychopharmacology. Mar 2013, 23 (3): 253–62. PMID 22658400. doi:10.1016/j.euroneuro.2012.04.010. 
  24. ^ Lane JR, Donthamsetti P, Shonberg J, Draper-Joyce CJ, Dentry S, Michino M, Shi L, López L, Scammells PJ, Capuano B, Sexton PM, Javitch JA, Christopoulos A. A new mechanism of allostery in a G protein–coupled receptor dimer. Nature Chemical Biology. Sep 2014, 10 (9): 745–52. PMID 25108820. doi:10.1038/nchembio.1593. 
  25. ^ Maggio R, Scarselli M, Capannolo M, Millan MJ. Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation. European Neuropsychopharmacology. Sep 2015, 25 (9): 1470–9. PMID 25453482. doi:10.1016/j.euroneuro.2014.09.016. 
  26. ^ Silvano E, Millan MJ, Mannoury la Cour C, Han Y, Duan L, Griffin SA, Luedtke RR, Aloisi G, Rossi M, Zazzeroni F, Javitch JA, Maggio R. The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors. Molecular Pharmacology. Nov 2010, 78 (5): 925–34. PMC 2981362. PMID 20702763. doi:10.1124/mol.110.065755. 
  27. ^ Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P. Functionally selective dopamine D₂, D₃ receptor partial agonists. Journal of Medicinal Chemistry. Jun 2014, 57 (11): 4861–75. PMID 24831693. doi:10.1021/jm5004039. 
  28. ^ Binda AV, Kabbani N, Lin R, Levenson R. D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N. Molecular Pharmacology. Sep 2002, 62 (3): 507–13. PMID 12181426. doi:10.1124/mol.62.3.507. 
  29. ^ Smith FD, Oxford GS, Milgram SL. Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein. The Journal of Biological Chemistry. Jul 1999, 274 (28): 19894–900. PMID 10391935. doi:10.1074/jbc.274.28.19894. 
  30. ^ Kabbani N, Negyessy L, Lin R, Goldman-Rakic P, Levenson R. Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor. The Journal of Neuroscience. Oct 2002, 22 (19): 8476–86. PMID 12351722. 
  31. ^ Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors - IUPHAR Review 13. British Journal of Pharmacology. Jan 2015, 172 (1): 1–23. PMC 4280963. PMID 25671228. doi:10.1111/bph.12906. 
  32. ^ Grandy DK, Miller GM, Li JX. "TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference. Drug Alcohol Depend. February 2016, 159: 9–16. PMID 26644139. doi:10.1016/j.drugalcdep.2015.11.014. This original observation of TAAR1 and DA D2R interaction has subsequently been confirmed and expanded upon with observations that both receptors can heterodimerize with each other under certain conditions ... Additional DA D2R/TAAR1 interactions with functional consequences are revealed by the results of experiments demonstrating that in addition to the cAMP/PKA pathway (Panas et al., 2012) stimulation of TAAR1-mediated signaling is linked to activation of the Ca++/PKC/NFAT pathway (Panas et al.,2012) and the DA D2R-coupled, G protein-independent AKT/GSK3 signaling pathway (Espinoza et al., 2015; Harmeier et al., 2015), such that concurrent TAAR1 and DA DR2R activation could result in diminished signaling in one pathway (e.g. cAMP/PKA) but retention of signaling through another (e.g., Ca++/PKC/NFA) 
  33. ^ Harmeier A, Obermueller S, Meyer CA, Revel FG, Buchy D, Chaboz S, Dernick G, Wettstein JG, Iglesias A, Rolink A, Bettler B, Hoener MC. Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers. Eur Neuropsychopharmacol. 2015, 25 (11): 2049–61. PMID 26372541. doi:10.1016/j.euroneuro.2015.08.011. Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity. 
  34. ^ Maggio R, Millan MJ. Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance. Current Opinion in Pharmacology. Feb 2010, 10 (1): 100–7. PMID 19896900. doi:10.1016/j.coph.2009.10.001. 
  35. ^ Hasbi A, O'Dowd BF, George SR. Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms. Current Opinion in Pharmacology. Feb 2010, 10 (1): 93–9. PMC 2818238. PMID 19897420. doi:10.1016/j.coph.2009.09.011. 
  36. ^ Albizu L, Holloway T, González-Maeso J, Sealfon SC. Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology. Sep 2011, 61 (4): 770–7. PMC 3556730. PMID 21645528. doi:10.1016/j.neuropharm.2011.05.023. 

外部連結[编辑]


多巴胺受體D2引用了美国国家医学图书馆提供的資料,这些資料属于公共领域

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