Dopamine receptor D4 explained

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

The structure of DRD4 has been 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] A weak association has been drawn between DRD4 and borderline personality disorder.

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:

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. 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] [34] and new evidence suggests that human encroachment may exert selection pressure in favor of DRD4 variants associated with novelty seeking.[35]

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.[36] [37] [38] However, antagonists of the D4 receptor reverse stress-induced or drug-induced working memory deficits.[39] [40] Gamma oscillations, which may be correlated with cognitive processing, can be increased by D4R agonists, but are not significantly reduced by D4R antagonists.[41] [42] [43]

Cognitive development

Several studies have suggested that parenting may affect the cognitive development of children with the 7-repeat allele of DRD4.[35] 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.[35] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.[35] Higher quality parenting was associated with better executive control in 4-year-olds.[35]

Ligands

Agonists

Antagonists

Inverse agonists

In popular culture

Michael Connelly’s 2020 crime novel Fair Warning (ISBN 978-0-316-53942-5) revolves around a serial killer who uses DNA profiles obtained on the Dark Web to target female victims, specifically those whose DRD4 profiles allegedly make them more susceptible to risk taking and sexual promiscuity.

See also

External links

Notes and References

  1. Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O . Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine . Nature . 350 . 6319 . 610–4 . April 1991 . 1840645 . 10.1038/350610a0 . 1991Natur.350..610V . 4244670 .
  2. Wang S, Wacker D, Levit A, Che T, Betz RM, McCorvy JD, Venkatakrishnan AJ, Huang XP, Dror RO, Shoichet BK, Roth BL . D4 dopamine receptor high-resolution structures enable the discovery of selective agonists . Science . 358 . 6361 . 381–386 . October 2017 . 29051383 . 5856174 . 10.1126/science.aan5468 . 2017Sci...358..381W .
  3. Ptácek R, Kuzelová H, Stefano GB . Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders . Medical Science Monitor . 17 . 9 . RA215–20 . September 2011 . 21873960 . 3560519 . 10.12659/MSM.881925 .
  4. Domschke K . Clinical and molecular genetics of psychotic depression . Schizophrenia Bulletin . 39 . 4 . 766–75 . July 2013 . 23512949 . 3686457 . 10.1093/schbul/sbt040 .
  5. LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL . Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder . Molecular Psychiatry . 1 . 2 . 121–4 . May 1996 . 9118321 .
  6. Smalley SL, Bailey JN, Palmer CG, Cantwell DP, McGough JJ, Del'Homme MA, Asarnow JR, Woodward JA, Ramsey C, Nelson SF . Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder . Molecular Psychiatry . 3 . 5 . 427–30 . September 1998 . 9774776 . 10.1038/sj.mp.4000457 . free .
  7. McGeary J . The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review . Pharmacology Biochemistry and Behavior . 93 . 3 . 222–9 . September 2009 . 19336242 . 2706302 . 10.1016/j.pbb.2009.03.010 .
  8. Cormier F, Muellner J, Corvol JC . Genetics of impulse control disorders in Parkinson's disease . Journal of Neural Transmission . 120 . 4 . 665–71 . April 2013 . 23232665 . 10.1007/s00702-012-0934-4 . 21967333 .
  9. Rask-Andersen M, Olszewski PK, Levine AS, Schiöth HB . Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake . Brain Research Reviews . 62 . 2 . 147–64 . March 2010 . 19931559 . 10.1016/j.brainresrev.2009.10.007 . 37635456 .
  10. Ptáček R, Kuželová H, Stefano GB, Raboch J, Kream RM . Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development . Current Drug Targets . 14 . 4 . 507–12 . April 2013 . 23469923 . 10.2174/1389450111314040012 .
  11. Neve KA, Seamans JK, Trantham-Davidson H . Dopamine receptor signaling . Journal of Receptor and Signal Transduction Research . 24 . 3 . 165–205 . August 2004 . 15521361 . 10.1081/RRS-200029981 . 10.1.1.465.5011 . 12407397 .
  12. Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V . Multiple dopamine D4 receptor variants in the human population . Nature . 358 . 6382 . 149–52 . July 1992 . 1319557 . 10.1038/358149a0 . 1992Natur.358..149T . 4345839 .
  13. Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E . Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients . Biological Psychiatry . 34 . 7 . 459–64 . October 1993 . 8268330 . 10.1016/0006-3223(93)90236-7 . 34841647 .
  14. Rondou P, Haegeman G, Van Craenenbroeck K . The dopamine D4 receptor: biochemical and signalling properties . Cellular and Molecular Life Sciences . 67 . 12 . 1971–86 . June 2010 . 20165900 . 10.1007/s00018-010-0293-y . 21432517 . 11115718 .
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  16. http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=94 Gene Overview of All Published Schizophrenia-Association Studies for DRD4
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  18. Wedemeyer C, Goutman JD, Avale ME, Franchini LF, Rubinstein M, Calvo DJ . Functional activation by central monoamines of human dopamine D(4) receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes . European Journal of Pharmacology . 562 . 3 . 165–73 . May 2007 . 17350612 . 10.1016/j.ejphar.2007.01.055 .
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  20. Faraone SV, Doyle AE, Mick E, Biederman J . Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder . The American Journal of Psychiatry . 158 . 7 . 1052–7 . July 2001 . 11431226 . 10.1176/appi.ajp.158.7.1052 .
  21. Yordanova J, Banaschewski T, Kolev V, Woerner W, Rothenberger A . Abnormal early stages of task stimulus processing in children with attention-deficit hyperactivity disorder--evidence from event-related gamma oscillations . Clinical Neurophysiology . 112 . 6 . 1096–108 . June 2001 . 11377270 . 10.1016/s1388-2457(01)00524-7. 19789570 .
  22. Demiralp T, Herrmann CS, Erdal ME, Ergenoglu T, Keskin YH, Ergen M, Beydagi H . DRD4 and DAT1 polymorphisms modulate human gamma band responses . Cerebral Cortex . 17 . 5 . 1007–19 . May 2007 . 16751296 . 10.1093/cercor/bhl011 . free .
  23. Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK . The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus . American Journal of Human Genetics . 74 . 5 . 931–44 . May 2004 . 15077199 . 1181986 . 10.1086/420854 .
  24. Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH . Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants . Journal of Neurochemistry . 65 . 3 . 1157–65 . September 1995 . 7643093 . 10.1046/j.1471-4159.1995.65031157.x . 23092115 .
  25. Chen CS, Burton M, Greenberger E, Dmitrieva J . Population Migration and the Variation of Dopamine D4 Receptor (DRD4) Allele Frequencies Around the Globe . Evolution and Human Behavior . 20 . 5 . 1999 . 309–24 . 10.1016/S1090-5138(99)00015-X . 12754148 .
  26. Eisenberg DT, Campbell B, Gray PB, Sorenson MD . Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: an exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya . BMC Evolutionary Biology . 8 . 173 . June 2008 . 18544160 . 2440754 . 10.1186/1471-2148-8-173 . free .
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