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Dopamine receptor D4

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(Redirected fromD4 receptor)
Protein-coding gene in the species Homo sapiens

DRD4
Identifiers
AliasesDRD4, D4DR, dopamine receptor D4
External IDsOMIM:126452;MGI:94926;HomoloGene:20215;GeneCards:DRD4;OMA:DRD4 - orthologs
Gene location (Human)
Chromosome 11 (human)
Chr.Chromosome 11 (human)[1]
Chromosome 11 (human)
Genomic location for DRD4
Genomic location for DRD4
Band11p15.5Start637,269bp[1]
End640,706bp[1]
Gene location (Mouse)
Chromosome 7 (mouse)
Chr.Chromosome 7 (mouse)[2]
Chromosome 7 (mouse)
Genomic location for DRD4
Genomic location for DRD4
Band7 F5|7 86.6 cMStart140,871,919bp[2]
End140,876,377bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • testicle

  • right uterine tube

  • pituitary gland

  • right hemisphere of cerebellum

  • left ovary

  • anterior pituitary

  • right ovary

  • primary visual cortex

  • sural nerve

  • body of uterus
Top expressed in
  • neural layer of retina

  • retinal pigment epithelium

  • epithelium of lens

  • decidua

  • seminiferous tubule

  • embryo

  • gastrula

  • embryo

  • iris

  • cumulus cell
More reference expression data
BioGPS
More reference expression data
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo /QuickGO
Orthologs
SpeciesHumanMouse
Entrez

1815

13491

Ensembl

ENSG00000069696
ENSG00000276825

ENSMUSG00000025496

UniProt

P21917

P51436

RefSeq (mRNA)

NM_000797

NM_007878

RefSeq (protein)

NP_000788

NP_031904

Location (UCSC)Chr 11: 0.64 – 0.64 MbChr 7: 140.87 – 140.88 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Thedopamine receptor D4 is a dopamineD2-likeG protein-coupled receptor encoded by theDRD4 gene onchromosome 11 at 11p15.5.[5]

The structure of DRD4 has been reported in complex with the antipsychotic drugnemonapride.[6]

As with otherdopamine receptor subtypes, the D4 receptor is activated by theneurotransmitterdopamine. It is linked to many neurological and psychiatric conditions[7] includingschizophrenia andbipolar disorder,[8]ADHD,[9][10] addictive behaviors,[11]Parkinson's disease,[12] andeating disorders such asanorexia nervosa.[13] A weak association has been drawn between DRD4 andborderline personality disorder.

It is also a target for drugs which treatschizophrenia andParkinson's disease.[14] The D4 receptor is considered to beD2-like in which the activated receptor inhibits the enzymeadenylate cyclase, thereby reducing the intracellular concentration of the second messengercyclic AMP.[15]

Genetics

[edit]

The human protein is coded by theDRD4 onchromosome 11 located in11p15.5.[16]

There are slight variations (mutations/polymorphisms) in the human gene:

Mutations in this gene have been associated with various behavioral phenotypes, includingautonomic nervous system dysfunction,attention deficit/hyperactivity disorder,[19]schizophrenia[20] and the personality trait ofnovelty seeking.[21]

48-base pair VNTR

[edit]

The 48-base pair variable number tandem repeat (VNTR) inexon 3 range from 2 to 11 repeats.[16] Dopamine is more potent at the D4 receptor with 2 allelic repeat or 7 allelic repeats than the variant with 4 allelic repeats.[22]

DRD4-7R, the 7-repeat (7R) variant ofDRD4 (DRD4 7-repeat polymorphism), has been linked to a susceptibility for developingADHD in several meta-analyses and other psychological traits and disorders.[23][24] Adults and children with the DRD4 7-repeat polymorphism show variations in auditory-evokedgamma oscillations, which may be related to attention processing.[25][26]

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.[27] In 1999 Chen and colleagues[29] 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 nomadicAriaal 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.[30]

Novelty seeking

[edit]

Despite early findings of an association between theDRD4 48bp VNTR andnovelty seeking (a normal characteristic of exploratory and excitable people),[31][32] a 2008meta-analysis compared 36 published studies of novelty seeking and the polymorphism and found no effect. Results are consistent with novelty-seeking behavior being acomplex trait associated with many genes, and the variance attributable toDRD4 by itself being very small. The meta-analysis of 11 studies did find that another polymorphism in the gene, the-521C/T, showed an association with novelty seeking.[21] While human results are not strong, research in animals has suggested stronger associations[33][34][35][36][37][38] and new evidence suggests that human encroachment may exert selection pressure in favor ofDRD4 variants associated with novelty seeking.[39][clarification needed]

Cognition

[edit]

Several studies have shown thatagonists that activate the D4 receptor increase working memory performance and fear acquisition in monkeys and rodents according to a U-shapeddose 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

[edit]

Several studies have suggested that parenting may affect thecognitive development of children with the 7-repeat allele ofDRD4.[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 betterexecutive control in 4-year-olds.[39]

Ligands

[edit]
Chemical structures of representative D4-preferring ligands.

Agonists

[edit]
  • WAY-100635: potent fullagonist, 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 and5HT1A
  • 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 andserotonergic weak antagonist
  • Nuciferine - D4 full selective but also partial D2 and D5 agonist

Antagonists

[edit]

Inverse agonists

[edit]

In popular culture

[edit]

Michael Connelly's 2020 crime novelFair Warning (ISBN 978-0-316-53942-5) revolves around a serial killer who uses DNA profiles obtained on theDark Web to target female victims, specifically those whose DRD4 profiles allegedly make them more susceptible to risk taking and sexual promiscuity.

See also

[edit]

References

[edit]
  1. ^abcENSG00000276825 GRCh38: Ensembl release 89: ENSG00000069696, ENSG00000276825 –Ensembl, May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000025496 –Ensembl, May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (April 1991). "Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine".Nature.350 (6319):610–4.Bibcode:1991Natur.350..610V.doi:10.1038/350610a0.PMID 1840645.S2CID 4244670.
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This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.

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