多巴胺受體D2
多巴胺受體D2(Dopamine receptor D2,簡稱D2R),為轉譯自 DRD2 基因的一種多巴胺受體蛋白。D2R最早於1975年為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)[8]。D2R為所有抗精神病藥物的作用標的。
功能
[編輯]D2R屬於一種多巴胺受體,並會與Gi結合。Gi為G蛋白偶聯受體的一種亞型,會抑制腺苷酸環化酶的活性[9]。
在小鼠模式中,齒狀回的neuronal calcium sensor-1(NCS-1)會影響D2R在細胞膜的表現量。這項機制會影響突觸可塑性及記憶形成[10]。
在蒼蠅模式中,多巴胺性神經元上的D2R自體受器能避免神經元死亡,進而引發類帕金森氏症的徵狀[11]。
同型體
[編輯]長形式(D2Lh)具有"規範"的序列,並作為經典突觸後蛋白發揮作用。[13]短形式(D2Sh)在突觸前作為調節突觸間隙中多巴胺水平的自身受體發揮作用。[13]D2Sh受體激動時抑制多巴胺釋放,拮抗時增加多巴胺釋放。[13]第三種D2(更長)的形式不同於270V被VVQ取代的規範序列。[14]
基因組
[編輯]等位基因變異:
- A-241G
- C132T、G423A、T765C、C939T、C957T,以及G1101A[15]
- Cys311Ser
- -141C insertion/deletion[16]The polymorphisms have been investigated with respect to association with schizophrenia.[17]
Some researchers have previously associated the polymorphism Taq 1A (rs1800497) to the DRD2 gene. However, the polymorphism resides in exon 8 of the ANKK1 gene.[18]DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.[19][20]
配體
[編輯]大多數較老的抗精神病藥如氯丙嗪或氟哌啶醇是多巴胺D2受體的非選擇性拮抗劑,最多僅對"D2樣家族"受體具有選擇性,因此與D2、D3、D4以及許多其他受體都可以結合,例如血清素和組織胺受體,導致一系列副作用使得它們不適合科學研究。類似,用於治療柏金遜症的較舊的多巴胺促效劑例如溴隱亭和卡麥角林,對一種多巴胺受體的選擇性較差,儘管這些藥物中大多數確實能起到D2促效劑的作用,但它們也會影響其他多巴胺受體,亞型也是。現今有幾種選擇性D2配體 (生物化學)可以使用,並且隨着進一步的研究,這個數字可能會增加。
受體致活劑
[編輯]- 溴隱亭(Bromocriptine):完全受體致活劑
- Cabergoline(Caberl)
- N,N-Propyldihydrexidine:D1/D5受體制活劑dihydrexidine的類似物,對節後神經元的D2R親和性比節前神經元的D2自體受器高。
- Piribedil:同時也是 D3 受體致活劑及腎上腺素α2受體拮抗劑
- Pramipexole:同時也是D3、D4受體致活劑
- Quinelorane:affinity for D2 > D3
- Quinpirole:同時也是D3受體致活劑
- Ropinirole:完全受體致活劑
- Sumanirole:高選擇性完全受體致活劑
- Talipexole:對D2的親和性高於其他的多巴胺受體,但同時也是腎上腺素α2受體制活劑及5-HT3受體拮抗劑。
部分受體致活劑
[編輯]- Aplindore
- 阿立哌唑(Aripiprazole,在美國合法)[21]
- Brexpiprazole/OPC-34712
- Cariprazine
- RP5063
- GSK-789,472 – Also D3 antagonist, with good selectivity over other receptors [22]
- 氯胺酮(Ketamine,同時也為NMDA受體拮抗劑)
- LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs.[23]LSD is also a 5-HT2A agonist.
- 莫達非尼(Modafinil)
- Roxindole (only at the D2 autoreceptors)
- OSU-6162:亦為5-HT2A部分受體致活劑,acts as "dopamine stabilizer"
- Salvinorin A:亦為κ-鴉片類受體致活劑。
受體拮抗劑
[編輯]- Atypical antipsychotics
- Desmethoxyfallypride
- Domperidone – D2 and D3 antagonist; does not cross the blood-brain barrier
- Eticlopride
- Fallypride
- Hydroxyzine (Vistaril, Atarax)
- Itopride
- L-741,626 – highly selective D2 antagonist
- C11 Raclopride radiolabled – commonly employed in positron emission tomography studies[24]
- Typical antipsychotics
- SV 293[25]
- Yohimbine
- D2sh selective (presynaptic autoreceptors)
變構調控因子
[編輯]Functionally selective ligands
[編輯]- 參見參考文獻[31]。
Protein–protein interactions
[編輯]多巴胺受體 D2 已被證明與EPB41L1、[32]PPP1R9B[33] 和 NCS-1 相互作用。[34]
Receptor oligomers
[編輯]The D2 receptor forms receptor heterodimers in vivo (in living animals) with other G protein-coupled receptors; these include:[35]
The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[38]DRD5,[39]and 5-HT2A.[40]
註釋
[編輯]- ^ 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–PKC–NFAT pathway and G-protein independent PKB–GSK3 pathway.[36][37]
參考文獻
[編輯]- ^ 與多巴胺受體D2相關的疾病;在維基數據上查看/編輯參考.
- ^ 對Dopamine receptor D2, isoform CRA_c起作用的藥物;在維基數據上查看/編輯參考.
- ^ 對Dopamine receptor D2起作用的藥物;在維基數據上查看/編輯參考.
- ^ 4.0 4.1 4.2 GRCh38: Ensembl release 89: ENSG00000149295 - Ensembl, May 2017
- ^ 5.0 5.1 5.2 GRCm38: Ensembl release 89: ENSMUSG00000032259 - Ensembl, May 2017
- ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Entrez Gene: DRD2 dopamine receptor D2. (原始內容存檔於2010-03-07).
- ^ 13.0 13.1 13.2 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.
- ^ UniProt P14416
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Clinical Pharmacology for Abilify. RxList.com. 2010-01-21 [2010-01-21]. (原始內容存檔於2010-01-18).
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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)
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
[編輯]- 醫學主題詞表(MeSH):Receptors,+Dopamine+D2
- Pappas, Stephanie. Study: Genes Influence Who Your Friends Are. Imaginova Corp. LiveScience. [20 January 2011].