多巴胺受体D₄

多巴胺受體D4
識別號
別名	DRD4；, D4DR, dopamine receptor D4
外部ID	OMIM：126452 MGI：94926 HomoloGene：20215 GeneCards：DRD4
為以下藥物的標靶
	PF-592379、羅替戈汀、A-412997、ABT-670、多巴胺、fenoldopam、quinpirole、WAY-100635、阿樸嗎啡、過乳降、麥角乙脲、培高利特、roxindole、溴隱亭、(+)-butaclamol、氯丙嗪、氯氮平、eticlopride、氟哌啶醇、L745870、洛沙平、5-chloro-2-methoxy-4-(methylamino)-N-(2-methyl-1-(phenylmethyl)-3-pyrrolidinyl)benzamide、perospirone、吡貝地爾、普樂明、sertindole、sonepiprazole、spiperone、levosulpiride、特麥角脲、三氟拉嗪、zotepine、匹莫齊特、氟哌利多、氟哌啶醇、阿樸嗎啡、thioridazine hydrochloride、bromocriptine mesylate、chlorpromazine hydrochloride、pergolide mesylate、promazine hydrochloride
基因位置（人類）
染色體	11號染色體
終止	640,706 bp
基因位置（小鼠）
染色體	小鼠7號染色體
終止	140,876,377 bp
RNA表達模式
	查閱更多表達數據
基因本體
分子功能	• signal transducer activity; • potassium channel regulator activity; • SH3 domain binding; • 相同蛋白質結合; • dopamine neurotransmitter receptor activity; • G protein-coupled receptor activity; • 血漿蛋白結合; • dopamine binding; • dopamine neurotransmitter receptor activity, coupled via Gi/Go; • 腎上腺素分泌; • norepinephrine binding; • 金屬離子結合; • G protein-coupled serotonin receptor activity; • neurotransmitter receptor activity;
細胞組分	• integral component of membrane; • integral component of plasma membrane; • 膜; • 細胞膜; • postsynapse; • glutamatergic synapse; • 樹突;
生物學過程	• response to amphetamine; • rhythmic process; • arachidonic acid secretion; • regulation of circadian rhythm; • positive regulation of dopamine uptake involved in synaptic transmission; • 訊息傳遞; • fear response; • dopamine metabolic process; • behavioral response to ethanol; • behavioral response to cocaine; • positive regulation of sodium:proton antiporter activity; • cellular calcium ion homeostasis; • positive regulation of kinase activity; • adult locomotory behavior; • 抑制性突觸; • negative regulation of protein secretion; • 社會行為; • negative regulation of voltage-gated calcium channel activity; • regulation of dopamine metabolic process; • response to histamine; • behavioral fear response; • dopamine receptor signaling pathway; • G protein-coupled receptor signaling pathway; • adenylate cyclase-inhibiting dopamine receptor signaling pathway; • regulation of postsynaptic neurotransmitter receptor internalization; • G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; • 化學性突觸傳遞; • G protein-coupled serotonin receptor signaling pathway;
	Sources:Amigo / QuickGO
直系同源
	1815
	13491
	ENSG00000069696; ENSG00000276825
	ENSMUSG00000025496
	P21917
	P51436
	NM_000797
	NM_007878
	NP_000788
	NP_031904
	維基數據
檢視/編輯人類	檢視/編輯小鼠

多巴胺受體D₄是一種由DRD4基因編碼的G蛋白偶聯受體。^[6]

和其他多巴胺受體亞型一樣, D₄受體由神經遞質——多巴胺激活。它與精神分裂症,帕金森症,躁鬱症，上癮行為，以及諸如厭食症, 貪食症和暴食症等神經性進食紊亂症等許多神經學或心理學狀況相關。

此受體也是許多治療精神分裂症和帕金森症的靶標. D₄受體被認為與D₂-類似，被激活的受體抑制腺甙酸環化酶，從而減少細胞內第二信息遞質環磷腺苷的濃度。^[7]

基因學[編輯]

此人體蛋白由 11號染色體上位於11p15.5的基因DRD4編碼。

人類基因中有輕微的變化（變異/多態)：

在外顯子3的一處48-鹼基對VNTR
啟動子中的C-521T
外顯子1中鹼基235至247的13-鹼基對刪除
外顯子I中12鹼基對重複。^[8]
Val194Gly
120bp處的多態串聯重複

此基因的變異與多種行為表型相關，包括自主神經系統失常，注意缺陷障礙，^[9] 精神分裂症,^[10] 以及尋求新奇的人格特徵。^[11]

48-鹼基對VNTR(可變數量串聯重複)[編輯]

外顯子3中的48-鹼基對可變數量串聯重複（VNTR）有2至11次重複。等位基因的頻率在人群中變化很大，例如，7-重複版本在美洲很高而在亞洲則很低。^[12] 「長」版本的多態基因是重複6到10次的等位基因。7R對多巴胺分子的反應強度似乎要略弱一些。^[13]

'長DRD4'變體, 或更具體地即7重複(7R)，鬆散地與形成ADHD ^[14] 以及其它的心理特徵和異常的易感性相關。

48-鹼基對VNTR已經成為了在跨文化環境下對其在人類行為的進化和角色方面所作出的諸多推測的主題。7R等位基因似乎在4萬年前就已經被選擇出來。^[12] 1999年，陳（音）及其同事^[15] 觀察到那些在過去3萬年到1萬年間遷移得比較遠的人類群體帶有7R/長等位基因的頻率較高。他們也指出遊牧人群帶有7R等位基因的頻率比定居人群高。較近期，也有觀察到擁有7R等位基因的游牧人阿里爾人健康狀況更好。然而，定居不久的（非游牧）帶有7R等位基因的阿里爾人似乎有輕微的健康退化狀況。^[16]

尋奇性格[編輯]

儘管有關於DRD4 48鹼基對VNTR與「尋奇性格」（具有愛探索和愛刺激人的一種性格特質）之間關聯的早期發現，^[17]^[18] 2008年的一項元分析對比了36份出版了的關於「尋奇性格」和多態性的研究，沒有找到有效相關性。關於11份研究的元分析確發現了基因的另一多態性——-521C/T顯示出與「尋奇性格」的聯繫。^[19] 。究其各種情況，「尋奇」行為可能是由幾個基因介導的，僅歸因於DRD4本身所造成的變化並不是特別大。

認知發展[編輯]

有一些研究指出育兒過程可能影響帶有DRD4 7-重複等位基因兒童的認知發展。^[20] 具有母性感受、正念和自治支持的育兒過程在15個月時對兒童後來在18至20個月的執行性功能有益^[20] 經歷較差育兒過程的兒童比那些有較好經歷者更衝動且更追求感官刺激。^[20]高質量的育兒過程與兒童在四歲時較好的努力控制相關。^[20]

配體[編輯]

激動劑[編輯]

WAY-100635: 全效激動劑, 帶有5-HT_1A拮抗組分^[21]
A-412,997: 完全激動劑, 對超過79種不同的受體和離子通道選擇性>100倍。^[22]
ABT-724 - 開發用於治療勃起功能障礙^[23]
ABT-670 - 比ABT-724口服生物利用率高^[24]
FAUC 316: 部分激動劑, 對其他多巴胺受體子類型選擇性>8600-fold倍^[25]
FAUC 299: 部分激動劑^[25]
(E)-1-芳基-3-(4-吡啶哌啶-1-基）丙酮肟^[26]
PIP3EA: 部分激動劑^[27]
Flibanserin - 部分激動劑
PD-168,077 - D₄選擇性但也綁定到α1A, α2C 和 5HT_1A
CP-226,269 - D₄選擇性但也綁定到D₂, D₃, α2A, α2C 和 5HT_1A
Ro10-5824 - 部分激動劑

受體拮抗劑[編輯]

A-381393: 強效，亞型選擇性拮抗劑 (>2700倍)^[28]
FAUC 213^[29]
L-745,870^[30]^[31]
L-750,667^[32]
S 18126: 也叫 σ1 affin^[33]
Fananserin - 混合型5-HT_2A / D₄ 拮抗劑
Clozapine，一種典型的抗精神病藥物

反激動劑[編輯]

FAUC F41: 反激動劑，亞型選擇性超過D₂和 D₃三個數量級^[29]^[34]

可參見[編輯]

精神病多巴胺假說

參考列表[編輯]

^ 對多巴胺受体D4起作用的藥物；在維基數據上查看/編輯參考.
^ ^2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000069696、ENSG00000276825 - Ensembl, May 2017
^ ^3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000025496 - 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.
^ Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. April 1991, 350 (6319): 610–4. PMID 1840645. doi:10.1038/350610a0.
^ Neve KA, Seamans JK, Trantham-Davidson H. Dopamine receptor signaling. J. Recept. Signal Transduct. Res. August 2004, 24 (3): 165–205. PMID 15521361. doi:10.1081/RRS-200029981.
^ Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E. Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients. Biol. Psychiatry. October 1993, 34 (7): 459–64. PMID 8268330. doi:10.1016/0006-3223(93)90236-7.
^ Thapar A, Langley K, Owen MJ, O'Donovan MC. Advances in genetic findings on attention deficit hyperactivity disorder. Psychol Med. December 2007, 37 (12): 1681–92. PMID 17506925. doi:10.1017/S0033291707000773.
^ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 （頁面存檔備份，存於網際網路檔案館） - SzGene database at Schizophrenia Research Forum.
^ Munafò MR, Yalcin B, Willis-Owen SA, Flint J. Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biol. Psychiatry. January 2008, 63 (2): 197–206. PMID 17574217. doi:10.1016/j.biopsych.2007.04.006.
^ ^12.0 ^12.1 Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK. The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am. J. Hum. Genet. May 2004, 74 (5): 931–44. PMC 1181986 . PMID 15077199. doi:10.1086/420854.
^ Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH. Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem. September 1995, 65 (3): 1157–1165. PMID 7643093. doi:10.1046/j.1471-4159.1995.65031157.x.
^ Faraone SV, Doyle AE, Mick E, Biederman J. Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. American Journal of Psychiatry. July 2001, 158 (7): 1052–7 [2013-02-15]. PMID 11431226. doi:10.1176/appi.ajp.158.7.1052. （原始內容存檔於2011-06-12）.
^ Chen CS, Burton M, Greenberger E, Dmitrieva J. Population migration and the variation of dopamine D4 receptor (DRD4) allele frequencies around the globe. Evolution and Human Behavior. September 1999, 20 (5): 309–324. doi:10.1016/S1090-5138(99)00015-X.
^ Eisenberg DT, Campbell B, Gray PB, Sorenson MD. Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: an exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya. BMC Evol. Biol. 2008, 8: 173. PMC 2440754 . PMID 18544160. doi:10.1186/1471-2148-8-173.
^ Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH. Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat. Genet. January 1996, 12 (1): 78–80. PMID 8528256. doi:10.1038/ng0196-78.
^ Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH. Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat. Genet. January 1996, 12 (1): 81–4. PMID 8528258. doi:10.1038/ng0196-81.
^ Munafo MR, Yalcin B, Willis-Owen SA, Flint J. Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biol Psychiatry. 2008, 63 (2): 197–206. PMID 17574217. doi:10.1016/j.biopsych.2007.04.006.
^ ^20.0 ^20.1 ^20.2 ^20.3 Posner MI, Rothbart MK, Sheese BE, Voelker P. Control networks and neuromodulators of early development. Dev Psychol. May 2012, 48 (3): 827–35. PMID 21942663. doi:10.1037/a0025530.
^ Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE. WAY-100635 is a potent dopamine D4 receptor agonist. Psychopharmacology (Berl.). 2006, 188 (2): 244–51. PMID 16915381. doi:10.1007/s00213-006-0490-4.
^ Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD. A-412997 is a selective dopamine D₄ receptor agonist in rats. Pharmacol. Biochem. Behav. 2005, 82 (1): 140–7. PMID 16153699. doi:10.1016/j.pbb.2005.08.001.
^ Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO. Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction. Journal of Medicinal Chemistry. July 2004, 47 (15): 3853–64. PMID 15239663. doi:10.1021/jm030505a.
^ Patel MV, Kolasa T, Mortell K; et al. Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction. J. Med. Chem. December 2006, 49 (25): 7450–65. PMID 17149874. doi:10.1021/jm060662k.
^ ^25.0 ^25.1 Hübner H, Kraxner J, Gmeiner P. Cyanoindole derivatives as highly selective dopamine D₄ receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments. J. Med. Chem. 2000, 43 (23): 4563–9. PMID 11087581. doi:10.1021/jm0009989.
^ Kolasa T, Matulenko MA, Hakeem AA; et al. 1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction. J. Med. Chem. August 2006, 49 (17): 5093–109. PMID 16913699. doi:10.1021/jm060279f.
^ Enguehard-Gueiffier C, Hübner H, El Hakmaoui A; et al. 2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist. J. Med. Chem. June 2006, 49 (13): 3938–47. PMID 16789750. doi:10.1021/jm060166w.
^ Nakane M, Cowart MD, Hsieh GC; et al. 2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist. Neuropharmacology. July 2005, 49 (1): 112–21. PMID 15992586. doi:10.1016/j.neuropharm.2005.02.004.
^ ^29.0 ^29.1 Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P. Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D₄ Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET. J. Med. Chem. 2008, 51 (6): 1800–10. PMID 18307287. doi:10.1021/jm701375u.
^ Kulagowski JJ, Broughton HB, Curtis NR; et al. 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J. Med. Chem. May 1996, 39 (10): 1941–2. PMID 8642550. doi:10.1021/jm9600712.
^ Patel S, Freedman S, Chapman KL; et al. Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. J. Pharmacol. Exp. Ther. 1 November 1997, 283 (2): 636–47. PMID 9353380.
^ Patel S, Patel S, Marwood R; et al. Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor. Mol. Pharmacol. December 1996, 50 (6): 1658–64. PMID 8967990.
^ Millan MJ, Newman-Tancredi A, Brocco M, Gobert A, Lejeune F, Audinot V, Rivet JM, Schreiber R, Dekeyne A, Spedding M, Nicolas JP, Peglion JL. S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride. J. Pharmacol. Exp. Ther. 1 October 1998, 287 (1): 167–86 [2013-02-15]. PMID 9765336. （原始內容存檔於2003-07-12）.
^ Lanig H, Utz W, Gmeiner P. Comparative molecular field analysis of dopamine D₄ receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine. J. Med. Chem. 2001, 44 (8): 1151–7. PMID 11312915. doi:10.1021/jm001055e.

外部連結[編輯]

Dopamine Receptors: D₄. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. （原始內容存檔於2012-03-05）.
Current Research on the DRD₄ Gene
醫學主題詞表（MeSH）：Receptors,+Dopamine+D4
Marisa Wilson. Are you a thrill seeker??. Davidson College. [2008-04-05]. （原始內容存檔於2008-01-05）.
The D4DR Gene. D4DR Club. [2008-04-05]. （原始內容存檔於2008-04-30）.

多巴胺受體D4引用了美國國家醫學圖書館提供的資料，這些資料屬於公共領域。

[1] 對多巴胺受体D4起作用的藥物；在維基數據上查看/編輯參考.

[refGRCh38Ensembl-2] 2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000069696、ENSG00000276825 - Ensembl, May 2017

[refGRCm38Ensembl-3] 3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000025496 - Ensembl, May 2017

[4] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid1840645-6] Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. April 1991, 350 (6319): 610–4. PMID 1840645. doi:10.1038/350610a0.

[pmid15521361-7] Neve KA, Seamans JK, Trantham-Davidson H. Dopamine receptor signaling. J. Recept. Signal Transduct. Res. August 2004, 24 (3): 165–205. PMID 15521361. doi:10.1081/RRS-200029981.

[pmid8268330-8] Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E. Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients. Biol. Psychiatry. October 1993, 34 (7): 459–64. PMID 8268330. doi:10.1016/0006-3223(93)90236-7.

[pmid17506925-9] Thapar A, Langley K, Owen MJ, O'Donovan MC. Advances in genetic findings on attention deficit hyperactivity disorder. Psychol Med. December 2007, 37 (12): 1681–92. PMID 17506925. doi:10.1017/S0033291707000773.

[SZGeneD4-10] Gene Overview of All Published Schizophrenia-Association Studies for DRD4 （頁面存檔備份，存於網際網路檔案館） - SzGene database at Schizophrenia Research Forum.

[pmid17574217-11] Munafò MR, Yalcin B, Willis-Owen SA, Flint J. Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biol. Psychiatry. January 2008, 63 (2): 197–206. PMID 17574217. doi:10.1016/j.biopsych.2007.04.006.

[pmid15077199-12] 12.0 ^12.1 Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK. The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am. J. Hum. Genet. May 2004, 74 (5): 931–44. PMC 1181986 . PMID 15077199. doi:10.1086/420854.

[pmid7643093-13] Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH. Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem. September 1995, 65 (3): 1157–1165. PMID 7643093. doi:10.1046/j.1471-4159.1995.65031157.x.

[pmid11431226-14] Faraone SV, Doyle AE, Mick E, Biederman J. Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. American Journal of Psychiatry. July 2001, 158 (7): 1052–7 [2013-02-15]. PMID 11431226. doi:10.1176/appi.ajp.158.7.1052. （原始內容存檔於2011-06-12）.

[Chen_1999-15] Chen CS, Burton M, Greenberger E, Dmitrieva J. Population migration and the variation of dopamine D4 receptor (DRD4) allele frequencies around the globe. Evolution and Human Behavior. September 1999, 20 (5): 309–324. doi:10.1016/S1090-5138(99)00015-X.

[pmid18544160-16] Eisenberg DT, Campbell B, Gray PB, Sorenson MD. Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: an exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya. BMC Evol. Biol. 2008, 8: 173. PMC 2440754 . PMID 18544160. doi:10.1186/1471-2148-8-173.

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