Dopamine receptor D4

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The dopamine receptor D4 is a dopamine D2-like G protein-coupled receptor encoded by the DRD4 gene on chromosome 11 at 11p15.5.[1]

The structure of DRD4 was recently reported in complex with the antipsychotic drug nemonapride.[2]

As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions[3] including schizophrenia and bipolar disorder,[4] ADHD,[5][6] addictive behaviors,[7] Parkinson's disease,[8] and eating disorders such as anorexia nervosa.[9]

It is also a target for drugs which treat schizophrenia and Parkinson's disease.[10] 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.[11]

Genetics

The human protein is coded by the DRD4 on chromosome 11 located in 11p15.5.[12]

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[13]
  • Val194Gly
  • A polymorphic tandem duplication of 48 bp[14]

Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder,[15] schizophrenia[16] and the personality trait of novelty seeking.[17]

48-base pair VNTR

The 48-base pair variable number tandem repeat (VNTR) in exon 3 range from 2 to 11 repeats.[12] Dopamine is more potent at the D4 receptor with 2 allelic repeat or 7 allelic repeats than the variant with 4 allelic repeats.[18]

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.[19][20] Adults and children with the DRD4 7-repeat polymorphism show variations in auditory-evoked gamma oscillations, which may be related to attention processing.[21][22]

The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.[23] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.[24]

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.[23] In 1999 Chen and colleagues[25] 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.[26]

Novelty seeking

Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a normal characteristic of exploratory and excitable people),[27][28] a 2008 meta-analysis compared 36 published studies of novelty seeking and the polymorphism and found no effect. Results are consistent with novelty-seeking behavior being a complex trait associated with many genes, and the variance attributable to DRD4 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.[17] While human results are not strong, research in animals has suggested stronger associations [29][30][31][32][33] and new evidence suggests that human encroachment may exert selection pressure in favor of DRD4 variants associated with novelty seeking.[34][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.[35][36][37] However, antagonists of the D4 receptor reverse stress-induced or drug-induced working memory deficits.[38][39] Gamma oscillations, which may be correlated with cognitive processing, can be increased by D4R agonists, but are not significantly reduced by D4R antagonists.[40][41][42]

Cognitive development

Several studies have suggested that parenting may affect the cognitive development of children with the 7-repeat allele of DRD4.[34] 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.[34] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.[34] Higher quality parenting was associated with better executive control in 4-year-olds.[34]

Ligands

Chemical structures of representative D4-preferring ligands.

Agonists

Antagonists

Inverse agonists

See also

References

  1. 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. doi:10.1038/350610a0. PMID 1840645.
  2. 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.
  3. 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 3560519. PMID 21873960.
  4. Domschke K (July 2013). "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin. 39 (4): 766–75. doi:10.1093/schbul/sbt040. PMC 3686457. PMID 23512949.
  5. 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.
  6. 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/sj.mp.4000457. PMID 9774776.
  7. 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 2706302. PMID 19336242.
  8. Cormier F, Muellner J, Corvol JC (April 2013). "Genetics of impulse control disorders in Parkinson's disease". Journal of Neural Transmission. 120 (4): 665–71. doi:10.1007/s00702-012-0934-4. PMID 23232665.
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External links

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