Dopamine receptor D4

Source: Wikipedia, the free encyclopedia.

DRD4
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
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

The dopamine receptor D4 is a dopamine

chromosome 11 at 11p15.5.[5]

The structure of DRD4 was recently reported in complex with the antipsychotic drug nemonapride.[6]

As with other

eating disorders such as anorexia nervosa.[13] A weak association has been drawn between DRD4 and borderline personality disorder
.

It is also a target for drugs which treat

Genetics

The human protein is coded by the DRD4 on

There are slight variations (

polymorphisms
) in the human gene:

Mutations in this gene have been associated with various behavioral phenotypes, including

attention deficit/hyperactivity disorder,[19] schizophrenia[20] and the personality trait of novelty seeking.[21]

48-base pair VNTR

The 48-base pair variable number tandem repeat (

VNTR) in exon 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 of DRD4 (DRD4 7-repeat polymorphism), has been linked to a susceptibility for developing

ADHD 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-evoked gamma 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.

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.[30]

Novelty seeking

Despite early findings of an association between the DRD4 48bp VNTR and

-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 of DRD4 variants associated with novelty seeking.[39][clarification needed
]

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

Chemical structures of representative D4-preferring 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

Inverse agonists

In popular culture

Dark Web
to target female victims, specifically those whose DRD4 profiles allegedly make them more susceptible to risk taking and sexual promiscuity.

See also

  • Dopamine hypothesis of psychosis

References

  1. ^ a b c ENSG00000276825 GRCh38: Ensembl release 89: ENSG00000069696, ENSG00000276825 - Ensembl, May 2017
  2. ^ a b c GRCm38: 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. S2CID 4244670
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External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.