多巴胺受体D4

位於11號人類染色體的基因

多巴胺受体D4是一种由DRD4基因编码的G蛋白偶联受体[6]

多巴胺受体D4
識別號
别名DRD4;, D4DR, dopamine receptor D4
外部IDOMIM126452 MGI94926 HomoloGene20215 GeneCardsDRD4
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、​loxapine、​nemonapride、​perospirone、​吡貝地爾、​普樂明、​sertindole、​sonepiprazole、​spiperone、​levosulpiride、​terguride、​三氟拉嗪、​zotepine[1]
基因位置(人类
11號染色體
染色体11號染色體[2]
11號染色體
多巴胺受体D4的基因位置
多巴胺受体D4的基因位置
基因座11p15.5起始637,269 bp[2]
终止640,706 bp[2]
RNA表达模式
PBB GE DRD4 208215 x at fs.png
查阅更多表达数据
直系同源
物種人類小鼠
Entrez
Ensembl
UniProt
mRNA​序列

NM_000797

NM_007878

蛋白序列

NP_000788

NP_031904

基因位置​(UCSC)Chr 11: 0.64 – 0.64 MbChr 7: 141.29 – 141.3 Mb
PubMed​查找[4][5]
維基數據
檢視/編輯人類檢視/編輯小鼠

和其他多巴胺受体亚型一样, D4受体由神经递质——多巴胺激活。它与精神分裂症,帕金森症,躁郁症,上瘾行为,以及诸如厌食症, 贪食症暴食症神经性进食紊乱症等许多神经学或心理学状况相关。

此受体也是许多治疗精神分裂症帕金森症的靶标. D4受体被认为与D2-类似,被激活的受体抑制腺甙酸环化酶,从而减少细胞内第二信息递质环磷腺苷 的浓度。[7]

基因学编辑

此人体蛋白由 11号染色体上位于11p15.5的基因DRD4编码。

人类基因中有轻微的变化(变异/多态):

  • 外显子3的一处48-碱基对VNTR
  • 启动子中的C-521T
  • 外显子1中碱基235至247的13-碱基对删除
  • 外显子I中12碱基对重复。[8]
  • Val194Gly
  • 120bp处的多态串联重复

此基因的变异与多种行为表型相关,包括自主神经系统失常,注意缺陷障碍[9] 精神分裂症,[10] 以及寻求新奇的人格特征。[11]

48-碱基对VNTR(可变数量串联重复)编辑

外显子3中的48-碱基对可变数量串联重复(VNTR)有2至11次重复。 等位基因的频率在人群中变化很大,例如,7-重复版本在美洲很高而在亚洲则很低。[12] “长”版本的多态基因是重复6到10次的等位基因。7R对多巴胺分子的反应强度似乎要略弱一些。[13]


'长DRD4'变体, 或更具体地即7重复(7R),松散地与形成ADHD [14] 以及其它的心理特征和异常的易感性相关。

48-碱基对VNTR已经成为了在跨文化环境下对其在人类行为的进化和角色方面所作出的诸多推测的主题。7R等位基因似乎在4万年前就已经被选择出来。[12] 1999年,陈(音)及其同事[15] 观察到那些在过去3万年到1万年间迁移得比较远的人类群体带有7R/长等位基因的频率较高。他们也指出游牧人群带有7R等位基因的频率比定居人群高。 较近期,也有观察到拥有7R等位基因的游牧人阿里尔人健康状况更好。然而,定居不久的(非游牧)带有7R等位基因的阿里尔人似乎有轻微的健康退化状况。[16]

寻奇性格编辑

尽管有关于DRD4 48碱基对VNTR与“寻奇性格”(具有爱探索和爱刺激人的一种性格特质)之间关联的早期发现,[17][18] 2008年的一项 元分析对比了36份出版了的关于“寻奇性格”和多态性的研究,没有找到有效相关性。关于11份研究的元分析确发现了基因的另一多态性——-521C/T显示出与“寻奇性格”的联系。[19] 。究其各种情况,“寻奇”行为可能是由几个基因介导的,仅归因于DRD4本身所造成的变化并不是特别大。

认知发展编辑

有一些研究指出育儿过程可能影响带有DRD4 7-重复等位基因儿童的认知发展[20] 具有母性感受、正念和自治支持的育儿过程在15个月时对儿童后来在18至20个月的执行性功能有益[20] 经历较差育儿过程的儿童比那些有较好经历者更冲动且更追求感官刺激。[20]高质量的育儿过程与儿童在四岁时较好的努力控制 相关。[20]

配体编辑

 
代表性的D4-常见配体的化学结构

激动剂编辑

  • WAY-100635: 全效 激动剂, 带有5-HT1A拮抗组分[21]
  • A-412,997: 完全激动剂, 对超过79种不同的受体和离子通道选择性>100倍。[22]
  • ABT-724 - 开发用于治疗勃起功能障碍[23]
  • ABT-670 - 比ABT-724口服生物利用率高[24]
  • FAUC 316: 部分激动剂, 对其他多巴胺受体子类型选择性>8600-fold倍[25]
  • FAUC 299: 部分激动剂[25]
  • (E)-1-芳基-3-(4-吡啶哌啶-1-基)丙酮肟[26]
  • PIP3EA: 部分激动剂[27]
  • Flibanserin - 部分激动剂
  • PD-168,077 - D4选择性但也绑定到α1A, α2C 和 5HT1A
  • CP-226,269 - D4选择性但也绑定到D2, D3, α2A, α2C 和 5HT1A
  • Ro10-5824 - 部分激动剂

受体拮抗剂编辑

反激动剂编辑

可参见编辑

参考列表编辑

  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. 
  2. ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000069696、ENSG00000276825 - Ensembl, May 2017
  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. 
  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. 
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  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. 
  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. 
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  33. ^ 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. (原始内容存档于2003-07-12). 
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外部链接编辑

多巴胺受体D4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