Dopamine receptor D4

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Dopamine receptor D4
Identifiers
SymbolsDRD4; D4DR
External IDsOMIM126452 MGI94926 HomoloGene20215 IUPHAR: D4 GeneCards: DRD4 Gene
RNA expression pattern
250px
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez181513491
EnsemblENSG00000069696ENSMUSG00000025496
UniProtP21917Q7TT80
RefSeq (mRNA)NM_000797NM_007878
RefSeq (protein)NP_000788NP_031904
Location (UCSC)Chr 11:
0.63 - 0.63 Mb
Chr 7:
141.14 - 141.15 Mb
PubMed search[1][2]

The dopamine receptor D4 is a G protein-coupled receptor encoded by the DRD4 gene.[1] As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions including schizophrenia, Parkinsons disease, bipolar disorder, addictive behaviors including sex addiction, and eating disorders such as anorexia nervosa, bulimia nervosa and binge eating. It is also a target for drugs which treat schizophrenia and Parkinson disease. The D4 receptor is considered to be D2-like in which the activated receptor inhibits the enzyme adenylate cyclase, thereby reducing the intracellular concentration of the second messenger cyclic AMP.[2]

Genetics

The human protein is coded by the DRD4 on chromosome 11 located in 11p15.5.

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

  • A 48-base pair VNTR in exon 3
  • C-521T in the promotor
  • 13-base pair deletion of bases 235 to 247 in exon 1
  • 12 base pair repeat in exon I.[3]
  • Val194Gly
  • A polymorphic tandem duplication of 120 bp

Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder,[4] schizophrenia,[5] and the personality trait of novelty seeking.[6]

48-base pair VNTR

The 48-base pair VNTR in exon 3 range from 2 to 11 repeats. The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.[7] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats.

The 'DRD4 long' variant, or more specifically the 7 repeat (7R), has been loosely linked to a susceptibility for developing ADHD[8] and other psychological traits and disorders, like autism and bulimia nervosa[9]

7R appears to react less strongly to dopamine molecules.[10].

The 48 bp 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.[7]. In 1999 Chen and colleagues[11] 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.[12]

Novelty seeking

In two studies published in Nature Genetics,[13][14] subjects filled out personality questionnaires and had blood taken for genetic analysis. The scientists found that those whose answers showed them to be exploratory and excitable — two hallmarks of novelty-seeking — also possessed a longer 7 repeat (7R) version of D4DR, compared with those who are more reserved and reflective. A few other studies have replicated these results (including two done in Japan) but at least one has found no such correlation. In any case, thrill-seeking behavior is probably mediated by several genes, and the variance attributable to D4DR by itself is not particularly large.

A 2002 meta-analysis compared 22 published studies of novelty seeking and the polymorphism and found a so small effect that the meta-analysis could not support the relationship. Instead the pointed to another polymorphism in the gene: the -521C/T which seemed to have a small effect on novelty seeking.[15]

Ligands

File:D4 ligands.png
Chemical structures of representative D4-preferring ligands.

Agonists

  • WAY-100635: potent full agonist, with 5-HT1A antagonistic component[16]
  • A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels[17]
  • ABT-724 - developed for treatment of erectile dysfunction[18]
  • ABT-670 - better oral bioavailability than ABT-724[19]
  • FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes[20]
  • FAUC 299: partial agonist[20]
  • (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes[21]
  • PIP3EA: partial agonist[22]
  • 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

Antagonists

Inverse agonists

See also

References

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External links

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

pt:Receptor D4 de dopamina ru:Дофаминовый рецептор D4
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