Dopamine receptor D4
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Location (UCSC) | Chr 11: 0.64 – 0.64 Mb | Chr 7: 140.87 – 140.88 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
The dopamine receptor D4 is a dopamine
The structure of DRD4 was recently reported in complex with the antipsychotic drug nemonapride.[6]
As with other
It is also a target for drugs which treat
Genetics
The human protein is coded by the DRD4 on
There are slight variations (
- A 48-base pair VNTR in exon3
- C-521T in the promoter
- 13-base pair deletion of bases 235 to 247 in exon 1
- 12 base pair repeat in exon 1[17]
- Val194Gly
- A polymorphic tandem duplication of 48 bp[18]
Mutations in this gene have been associated with various behavioral phenotypes, including
48-base pair VNTR
The 48-base pair variable number tandem repeat (
DRD4-7R, the 7-repeat (7R) variant of DRD4 (DRD4 7-repeat polymorphism), has been linked to a susceptibility for developing
The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.[27] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.[28]
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.
Novelty seeking
Despite early findings of an association between the DRD4 48bp VNTR and
Cognition
Several studies have shown that agonists that activate the D4 receptor increase working memory performance and fear acquisition in monkeys and rodents according to a U-shaped dose response curve.[40][41][42] However, antagonists of the D4 receptor reverse stress-induced or drug-induced working memory deficits.[43][44] Gamma oscillations, which may be correlated with cognitive processing, can be increased by D4R agonists, but are not significantly reduced by D4R antagonists.[45][46][47]
Cognitive development
Several studies have suggested that parenting may affect the cognitive development of children with the 7-repeat allele of DRD4.[39] Parenting that has maternal sensitivity, mindfulness, and autonomy–support at 15 months was found to alter children's executive functions at 18 to 20 months.[39] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.[39] Higher quality parenting was associated with better executive control in 4-year-olds.[39]
Ligands
Agonists
- WAY-100635: potent full agonist, with 5-HT1A antagonistic component[48]
- A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels[49]
- ABT-724 - developed for treatment of erectile dysfunction[50]
- ABT-670 - better oral bioavailability than ABT-724[51]
- FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes[52]
- FAUC 299: partial agonist[52]
- F-15063: antipsychotic with partial D4 agonism
- (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes[53]
- PIP3EA: partial agonist[54]
- Flibanserin - partial agonist
- PD-168,077 - D4 selective but also binds to α1A, α2C and 5HT1A
- CP-226,269 - D4 selective but also binds to D2, D3, α2A, α2C and 5HT1A
- Ro10-5824 – partial agonist
- Roxindole – D4 selective but also D2 and D3 autoreceptor agonist, 5HT1A receptor agonist, serotonin reuptake inhibitor)
- Apomorphine – D4 selective but also D2 and D3 agonist, α-adrenergic and serotonergic weak antagonist
- Nuciferine - D4 full selective but also partial D2 and D5 agonist
Antagonists
- A-381393: potent, subtype selective antagonist (>2700-fold)[55]
- FAUC 213[56]
- L-745,870[57][58]
- L-750,667[59]
- ML-398[60]
- S 18126 - also σ1 affinity[61]
- Fananserin – mixed 5-HT2A / D4 antagonist
- Olanzapine, an atypical antipsychotic
- Buspirone, an anxiolytic
Inverse agonists
- FAUC F41: inverse agonist, subtype selectivity of more than 3 orders of magnitude over D2 and D3[56][62]
In popular culture
See also
- Dopamine hypothesis of psychosis
References
- ^ a b c ENSG00000276825 GRCh38: Ensembl release 89: ENSG00000069696, ENSG00000276825 - Ensembl, May 2017
- ^ a b c 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.
- S2CID 4244670.
- PMID 29051383.
- PMID 21873960.
- PMID 23512949.
- PMID 9118321.
- PMID 9774776.
- PMID 19336242.
- S2CID 21967333.
- S2CID 37635456.
- PMID 23469923.
- S2CID 12407397.
- ^ S2CID 4345839.
- S2CID 34841647.
- S2CID 21432517.
- S2CID 20556855.
- SzGene database at Schizophrenia Research Forum.
- ^ S2CID 28997438.
- PMID 17350612.
- S2CID 895006.
- PMID 11431226.
- S2CID 19789570.
- PMID 16751296.
- ^ PMID 15077199.
- S2CID 23092115.
- S2CID 12754148.
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- S2CID 27276401.
- S2CID 24226671.
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- S2CID 10576133.
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- PMID 24833999.
- PMID 17986156.
- .
- ^ PMID 21942663.
- S2CID 21960608.
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- S2CID 36272297.
- S2CID 24469748.
- PMID 10989267.
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- PMID 23839116.
- S2CID 17141380.
- S2CID 24194034.
- S2CID 10270715.
- PMID 15239663.
- PMID 17149874.
- ^ PMID 11087581.
- PMID 16913699.
- PMID 16789750.
- S2CID 7529599.
- ^ PMID 18307287.
- PMID 8642550.
- PMID 9353380.
- PMID 8967990.
- PMID 25221667.
- PMID 9765336.
- PMID 11312915.
External links
- "Dopamine Receptors: D4". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 5 March 2012. Retrieved 4 December 2008.
- Current Research on the DRD4 Gene
- Receptors,+Dopamine+D4 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Marisa Wilson. "Are you a thrill seeker??". Davidson College. Retrieved 5 April 2008.
- "The D4DR Gene". D4DR Club. Archived from the original on 13 October 2007. Retrieved 5 April 2008.
- Overview of all the structural information available in the PDB for UniProt: P21917 (D(4) dopamine receptor) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.