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D4 receptor

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D4 receptor

Dopamine receptor D4
Identifiers
DRD4 Gene
RNA expression pattern

The dopamine receptor D4 is a 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, 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 promoter
  • 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. 7R appears to react less strongly to dopamine molecules.[8]

The 'DRD4 long' variant, or more specifically the 7 repeat (7R), has been linked to a susceptibility for developing ADHD in several meta-analyses [9] [10] and other psychological traits and disorders.

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.[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

Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a characteristic of exploratory and excitable people),[13][14] 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.[15] In any case, novelty-seeking behavior is probably mediated by several genes, and the variance attributable to DRD4 by itself is not particularly large.

Cognitive development

Several studies have suggested that parenting may affect the cognitive development of children with the 7-repeat allele of DRD4.[16] 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.[16] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.[16] Higher quality parenting was associated with better effortful control in 4-year-olds.[16]

Ligands


Agonists

  • WAY-100635: potent full agonist, with 5-HT1A antagonistic component[17]
  • A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels[18]
  • ABT-724 - developed for treatment of erectile dysfunction[19]
  • ABT-670 - better oral bioavailability than ABT-724[20]
  • FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes[21]
  • FAUC 299: partial agonist[21]
  • (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes[22]
  • PIP3EA: partial agonist[23]
  • 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

External links

  • Gene
  • Medical Subject Headings (MeSH)

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

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