Dopamine receptor D4

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Aliases DRD4, D4DR, dopamine receptor D4
External IDs MGI: 94926 HomoloGene: 20215 GeneCards: DRD4
Gene location (Human)
Chromosome 11 (human)
Chr. Chromosome 11 (human)[1]
Chromosome 11 (human)
Genomic location for DRD4
Genomic location for DRD4
Band 11p15.5 Start 637,293 bp[1]
End 640,706 bp[1]
RNA expression pattern
PBB GE DRD4 208215 x at fs.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 11: 0.64 – 0.64 Mb Chr 11: 141.29 – 141.3 Mb
PubMed search [3] [4]
View/Edit Human View/Edit Mouse

The dopamine receptor D4 is a G protein-coupled receptor encoded by the DRD4 gene on chromosome 11 at 11p15.5.[5]

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

As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions[7] including schizophrenia and bipolar disorder,[8] ADHD,[9][10] addictive behaviors,[11] Parkinson's disease,[12] and eating disorders such as anorexia nervosa.[13]

It is also a target for drugs which treat schizophrenia and Parkinson disease.[14] 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.[15]


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

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 1.[16]
  • Val194Gly
  • A polymorphic tandem duplication of 120 bp[citation needed]

Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder,[17] schizophrenia[18] and the personality trait of novelty seeking.[19]

48-base pair VNTR [edit]

The 48-base pair variable number tandem repeat (VNTR) in exon 3 range from 2 to 11 repeats.[citation needed]

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.[20][21]

The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.[22] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.[23]

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.[22] In 1999 Chen and colleagues[24] 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.[25]

Novelty seeking[edit]

Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a normal characteristic of exploratory and excitable people),[26][27] 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.[19] While human results are controversial, an increasing body of animal evidence has linked DRD4 variants with novelty seeking,[28][29][30][31][32] and new evidence suggests that human encroachment may exert selection pressure in favor of DRD4 variants associated with novelty seeking.[33] Novelty-seeking behavior is probably mediated by several genes, and the variance attributable to DRD4 by itself is not particularly large.[citation needed]

Cognitive development[edit]

Several studies have suggested that parenting may affect the cognitive development of children with the 7-repeat allele of DRD4.[33] 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.[33] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.[33] Higher quality parenting was associated with better executive control in 4-year-olds.[33]


Chemical structures of representative D4-preferring ligands.



Inverse agonists[edit]

See also[edit]


  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:". 
  4. ^ "Mouse PubMed Reference:". 
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  6. ^ Wang S, Wacker D, Levit A, Che T, Betz RM, McCorvy JD, Venkatakrishnan AJ, Huang XP, Dror RO, Shoichet BK, Roth BL (October 2017). "D4 dopamine receptor high-resolution structures enable the discovery of selective agonists". Science. 358 (6361): 381–386. doi:10.1126/science.aan5468. PMID 29051383. 
  7. ^ Ptácek R, Kuzelová H, Stefano GB (September 2011). "Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders". Medical Science Monitor. 17 (9): RA215–20. doi:10.12659/MSM.881925. PMC 3560519Freely accessible. PMID 21873960. 
  8. ^ Domschke K (July 2013). "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin. 39 (4): 766–75. doi:10.1093/schbul/sbt040. PMC 3686457Freely accessible. PMID 23512949. 
  9. ^ LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL (May 1996). "Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder". Molecular Psychiatry. 1 (2): 121–4. PMID 9118321. 
  10. ^ Smalley SL, Bailey JN, Palmer CG, Cantwell DP, McGough JJ, Del'Homme MA, Asarnow JR, Woodward JA, Ramsey C, Nelson SF (September 1998). "Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder". Molecular Psychiatry. 3 (5): 427–30. doi:10.1038/ PMID 9774776. 
  11. ^ McGeary J (September 2009). "The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review". Pharmacology Biochemistry and Behavior. 93 (3): 222–9. doi:10.1016/j.pbb.2009.03.010. PMC 2706302Freely accessible. PMID 19336242. 
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External links[edit]

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