多巴胺受体D4：修订间差异
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* [[Val194Gly]] |
* [[Val194Gly]] |
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* 120bp处的多态串联重复 |
* 120bp处的多态串联重复 |
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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]]，<ref name="pmid17506925">{{cite journal | author = Thapar A, Langley K, Owen MJ, O'Donovan MC | title = Advances in genetic findings on attention deficit hyperactivity disorder | journal = Psychol Med | volume = 37 | issue = 12 | pages = 1681–92 | year = 2007 | month = December | pmid = 17506925 | doi = 10.1017/S0033291707000773 | url = }}</ref> [[schizophrenia]],<ref name="SZGeneD4">[http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=94 Gene Overview of All Published Schizophrenia-Association Studies for DRD4] - [[SzGene]] database at [[Schizophrenia Research Forum]].</ref> and the personality trait of [[novelty seeking]].<ref name="pmid17574217">{{cite journal | author = Munafò MR, Yalcin B, Willis-Owen SA, Flint J | title = Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data | journal = Biol. Psychiatry | volume = 63 | issue = 2 | pages = 197–206 | year = 2008 | month = January | pmid = 17574217 | doi = 10.1016/j.biopsych.2007.04.006 | url = }}</ref> |
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=== 48-碱基对VNTR(可变数量串联重复) === |
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The 48-base pair [[VNTR]] in [[exon]] 3 range from 2 to 11 repeats. |
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The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.<ref name="pmid15077199">{{cite journal | author = Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK | title = The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus | journal = Am. J. Hum. Genet. | volume = 74 | issue = 5 | pages = 931–44 | year = 2004 | month = May | pmid = 15077199 | pmc = 1181986 | doi = 10.1086/420854 | url = }}</ref> "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.<ref name="pmid7643093">{{cite journal |
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| author = Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH |
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| title = Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants |
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| journal = J Neurochem |
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| volume = 65 | issue = 3 | pages = 1157–1165 |
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| year = 1995 | month = September |
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| pmid = 7643093 |
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| doi = 10.1046/j.1471-4159.1995.65031157.x |
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}}</ref> |
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The 'DRD4 long' variant, or more specifically the 7 repeat (7R), has been loosely linked to a susceptibility for developing [[ADHD]]<ref name="pmid11431226">{{cite journal |
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| author = [[Stephen V. Faraone|Faraone SV]], Doyle AE, Mick E, Biederman J |
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| title = Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder |
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| journal = [[American Journal of Psychiatry]] |
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| volume = 158 | issue = 7 | pages = 1052–7 |
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| year = 2001 | month = July | pmid = 11431226 |
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| doi = 10.1176/appi.ajp.158.7.1052 |
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| url = http://ajp.psychiatryonline.org/cgi/content/full/158/7/1052 |
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}}</ref> |
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and other psychological traits and disorders. |
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The 48-base pair VNTR has been the subject of much speculation about its evolution and role in human behaviors cross-culturally. The 7R allele appears to have been selected for about 40,000 years ago.<ref name="pmid15077199"/> In 1999 Chen and colleagues<ref name="Chen_1999">{{cite journal | author = Chen CS, Burton M, Greenberger E, Dmitrieva J | title = Population migration and the variation of dopamine D4 receptor (DRD4) allele frequencies around the globe | journal = Evolution and Human Behavior | volume = 20 | issue = 5 | pages = 309–324 | year = 1999 | month = September | pmid = | doi = 10.1016/S1090-5138(99)00015-X | url = }}</ref> observed that populations who migrated farther in the past 30,000 to 1,000 years ago had a higher frequency of 7R/long alleles. They also showed that nomadic populations had higher frequencies of 7R alleles than sedentary ones. More recently it was observed that the health status of nomadic [[Ariaal]] men was higher if they had 7R alleles. However in recently sedentary (non-nomadic) Ariaal those with 7R alleles seemed to have slightly deteriorated health.<ref name="pmid18544160">{{cite journal | author = Eisenberg DT, Campbell B, Gray PB, Sorenson MD | title = 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 | journal = BMC Evol. Biol. | volume = 8| pages = 173 | year = 2008 | pmid = 18544160 | pmc = 2440754 | doi = 10.1186/1471-2148-8-173 | url = }}</ref> |
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==寻奇性格== |
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Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a characteristic of exploratory and excitable people),<ref name="pmid8528256">{{cite journal | author = Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH | title = Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking | journal = Nat. Genet. | volume = 12 | issue = 1 | pages = 78–80 | year = 1996 | month = January | pmid = 8528256 | doi = 10.1038/ng0196-78 }}</ref><ref name="pmid8528258">{{cite journal | author = Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH | title = Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking | journal = Nat. Genet. | volume = 12 | issue = 1 | pages = 81–4 | year = 1996 | month = January | pmid = 8528258 | doi = 10.1038/ng0196-81 }}</ref> a 2008 [[meta-analysis]] compared 36 published studies of novelty seeking and the polymorphism and found no effect. The meta-analysis of 11 studies did find that another polymorphism in the gene, the [[-521C/T]], showed an association with novelty seeking.<ref name>{{cite journal | author = Munafo MR, Yalcin B, Willis-Owen SA, Flint J. | title = Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data | journal =Biol Psychiatry | volume = 63| issue = 2| pages = 197–206 | year = 2008 | doi = 10.1016/j.biopsych.2007.04.006 | pmid = 17574217}}</ref> In any case, novelty-seeking behavior is probably mediated by several genes, and the variance attributable to DRD4 by itself is not particularly large. |
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==认知发展== |
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Several studies have suggested that parenting may affect the [[cognitive development]] of children with the 7-repeat allele of DRD4.<ref name="Posner">{{cite journal | author = Posner MI, Rothbart MK, Sheese BE, Voelker P | title = Control networks and neuromodulators of early development | journal = Dev Psychol | volume = 48 | issue = 3 | pages = 827–35 | year = 2012 | month = May | pmid = 21942663 | doi = 10.1037/a0025530 }}</ref> Parenting that has maternal sensitivity, mindfulness, and autonomy–support at 15 months was found to children's later executive functions at 18 to 20 months.<ref name=Posner/> Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.<ref name=Posner/> Higher quality parenting was associated with better [[effortful control]] in 4-year-olds.<ref name=Posner/> |
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==配体== |
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[[Image:D4 ligands.png|thumbnail|right|400px|Chemical structures of representative D<sub>4</sub>-preferring ligands.]] |
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PMID 10479303 |
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PMID 9406594 |
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PMID 9276014 |
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PMID 8968364 |
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PMID 9871530 |
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PMID 12362366 |
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===激动剂=== |
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* [[WAY-100635]]: potent full [[agonist]], with 5-HT<sub>1A</sub> antagonistic component<ref name="pmid16915381">{{cite journal | author = Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE | title = WAY-100635 is a potent dopamine D4 receptor agonist | journal = Psychopharmacology (Berl.) | volume = 188 | issue = 2 | pages = 244–51 | year = 2006 | pmid = 16915381 | doi = 10.1007/s00213-006-0490-4 }}</ref> |
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* [[A-412,997]]: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels<ref name="pmid16153699">{{cite journal | author = Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD | title = A-412997 is a selective dopamine D<sub>4</sub> receptor agonist in rats | journal = Pharmacol. Biochem. Behav. | volume = 82 | issue = 1 | pages = 140–7 | year = 2005 | pmid = 16153699 | doi = 10.1016/j.pbb.2005.08.001 }}</ref> |
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* [[ABT-724]] - developed for treatment of erectile dysfunction<ref name="pmid15239663">{{cite journal |author=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 |title=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=Journal of Medicinal Chemistry |volume=47 |issue=15 |pages=3853–64 |year=2004 |month=July |pmid=15239663 |doi=10.1021/jm030505a |url=}}</ref> |
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* [[ABT-670]] - better oral bioavailability than ABT-724<ref>{{cite journal |author=Patel MV, Kolasa T, Mortell K, ''et al.'' |title=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 |journal=J. Med. Chem. |volume=49 |issue=25 |pages=7450–65 |year=2006 |month=December |pmid=17149874 |doi=10.1021/jm060662k}}</ref> |
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* FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes<ref name="pmid11087581">{{cite journal | author = Hübner H, Kraxner J, Gmeiner P | title = Cyanoindole derivatives as highly selective dopamine D<sub>4</sub> receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments | journal = J. Med. Chem. | volume = 43 | issue = 23 | pages = 4563–9 | year = 2000 | pmid = 11087581 | doi = 10.1021/jm0009989 }}</ref> |
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* FAUC 299: partial agonist<ref name="pmid11087581"/> |
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* (''E'')-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes<ref>{{cite journal |author=Kolasa T, Matulenko MA, Hakeem AA, ''et al.'' |title=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 |journal=J. Med. Chem. |volume=49 |issue=17 |pages=5093–109 |year=2006 |month=August |pmid=16913699 |doi=10.1021/jm060279f}}</ref> |
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* PIP3EA: partial agonist<ref>{{cite journal |author=Enguehard-Gueiffier C, Hübner H, El Hakmaoui A, ''et al.'' |title=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 |journal=J. Med. Chem. |volume=49 |issue=13 |pages=3938–47 |year=2006 |month=June |pmid=16789750 |doi=10.1021/jm060166w}}</ref> |
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* [[Flibanserin]] - partial agonist |
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* [[PD-168,077]] - D<sub>4</sub> selective but also binds to α1A, α2C and 5HT<sub>1A</sub> |
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* [[CP-226,269]] - D<sub>4</sub> selective but also binds to D<sub>2</sub>, D<sub>3</sub>, α2A, α2C and 5HT<sub>1A</sub> |
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* [[Ro10-5824]] - partial agonist |
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===受体拮抗剂=== |
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* A-381393: potent, subtype selective [[receptor antagonist|antagonist]] (>2700-fold)<ref>{{cite journal |author=Nakane M, Cowart MD, Hsieh GC, ''et al.'' |title=2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist |journal=Neuropharmacology |volume=49 |issue=1 |pages=112–21 |year=2005 |month=July |pmid=15992586 |doi=10.1016/j.neuropharm.2005.02.004}}</ref> |
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* FAUC 213<ref name = "pmid18307287"/> |
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* [[L-745,870]]<ref>{{cite journal |author=Kulagowski JJ, Broughton HB, Curtis NR, ''et al.'' |title=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 |journal=J. Med. Chem. |volume=39 |issue=10 |pages=1941–2 |year=1996 |month=May |pmid=8642550 |doi=10.1021/jm9600712}}</ref><ref>{{cite journal |author=Patel S, Freedman S, Chapman KL, ''et al.'' |title=Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor |journal=J. Pharmacol. Exp. Ther. |volume=283 |issue=2 |pages=636–47 |date=1 November 1997|pmid=9353380 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9353380 }}</ref> |
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* L-750,667<ref>{{cite journal |author=Patel S, Patel S, Marwood R, ''et al.'' |title=Identification and pharmacological characterization of <nowiki>[125I]</nowiki>L-750,667, a novel radioligand for the dopamine D4 receptor |journal=Mol. Pharmacol. |volume=50 |issue=6 |pages=1658–64 |year=1996 |month=December |pmid=8967990 |url=http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8967990}}</ref> |
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* S 18126: also σ1 affin<ref name="pmid9765336">{{cite journal | author = 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 | title =<nowiki> 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</nowiki> | journal = J. Pharmacol. Exp. Ther. | volume = 287 | issue = 1 | pages = 167–86 | date=1 October 1998| pmid = 9765336 | url = http://jpet.aspetjournals.org/cgi/content/abstract/287/1/167 | issn = }}</ref> |
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* [[Fananserin]] - mixed 5-HT<sub>2A</sub> / D<sub>4</sub> antagonist |
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* [[Clozapine]], an atypical antipsychotic |
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===反激动剂=== |
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* FAUC F41: [[inverse agonist]], subtype selectivity of more than 3 orders of magnitude over D<sub>2</sub> and D<sub>3</sub><ref name="pmid18307287">{{cite journal | author = Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P | title = Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D<sub>4</sub> Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET | journal = J. Med. Chem. | volume = 51| issue = 6| pages = 1800–10| year = 2008 | pmid = 18307287 | doi = 10.1021/jm701375u }}</ref><ref name="pmid11312915">{{cite journal | author = Lanig H, Utz W, Gmeiner P | title = Comparative molecular field analysis of dopamine D<sub>4</sub> 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 | journal = J. Med. Chem. | volume = 44 | issue = 8 | pages = 1151–7 | year = 2001 | pmid = 11312915 | doi = 10.1021/jm001055e }}</ref> |
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==可参见== |
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* [[精神病多巴胺假说]] |
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==参考列表== |
==参考列表== |
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{{Reflist}} |
{{Reflist|2}} |
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==外部链接== |
==外部链接== |
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2013年2月15日 (五) 05:30的版本
多巴胺受体D4是一种由DRD4基因编码的G蛋白偶联受体。[1]
和其他多巴胺受体子类型一样, 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, 贪食症和暴食症等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和帕金森症的靶标. 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。[2]
基因学
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)：
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，[4] schizophrenia,[5] and the personality trait of novelty seeking.[6]
48-碱基对VNTR(可变数量串联重复)
寻奇性格
认知发展
配体
激动剂
受体拮抗剂
反激动剂
可参见
参考列表
- ^ 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. 1991, 350 (6319): 610–4. PMID 1840645. doi:10.1038/350610a0. 已忽略未知参数
|month=（建议使用|date=） (帮助) - ^ Neve KA, Seamans JK, Trantham-Davidson H. Dopamine receptor signaling. J. Recept. Signal Transduct. Res. 2004, 24 (3): 165–205. PMID 15521361. doi:10.1081/RRS-200029981. 已忽略未知参数
|month=（建议使用|date=） (帮助) - ^ 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. 1993, 34 (7): 459–64. PMID 8268330. doi:10.1016/0006-3223(93)90236-7. 已忽略未知参数
|month=（建议使用|date=） (帮助) - ^ Thapar A, Langley K, Owen MJ, O'Donovan MC. Advances in genetic findings on attention deficit hyperactivity disorder. Psychol Med. 2007, 37 (12): 1681–92. PMID 17506925. doi:10.1017/S0033291707000773. 已忽略未知参数
|month=（建议使用|date=） (帮助) - ^ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 - 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. 2008, 63 (2): 197–206. PMID 17574217. doi:10.1016/j.biopsych.2007.04.006. 已忽略未知参数
|month=（建议使用|date=） (帮助)
外部链接
- Dopamine Receptors: D4. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- 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].
- The D4DR Gene. D4DR Club. [2008-04-05].
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。
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