Biology:Dopamine receptor D4

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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] 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:

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

Chemical structures of representative D4-preferring ligands.

Agonists

  • WAY-100635: potent full agonist, with 5-HT1A antagonistic component[44]
  • A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels[45]
  • ABT-724 - developed for treatment of erectile dysfunction[46]
  • ABT-670 - better oral bioavailability than ABT-724[47]
  • FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes[48]
  • FAUC 299: partial agonist[48]
  • F-15063: antipsychotic with partial D4 agonism
  • (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes[49]
  • PIP3EA: partial agonist[50]
  • 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
  • Roxindole – D4 selective but also D2 and D3 autoreceptor agonist, 5HT1A receptor agonist, serotonin reuptake inhibitor)
  • Apomorphine – D4 selective but also D2 and D3 agonist, α-adrenergic and serotonergic weak antagonist
  • Nuciferine - D4 full selective but also partial D2 and D5 agonist

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

  • Dopamine hypothesis of psychosis

References

  1. ↑ "Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine". Nature 350 (6319): 610–4. April 1991. doi:10.1038/350610a0. PMID 1840645. Bibcode: 1991Natur.350..610V. 
  2. ↑ "D4 dopamine receptor high-resolution structures enable the discovery of selective agonists". Science 358 (6361): 381–386. October 2017. doi:10.1126/science.aan5468. PMID 29051383. Bibcode: 2017Sci...358..381W. 
  3. ↑ "Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders". Medical Science Monitor 17 (9): RA215–20. September 2011. doi:10.12659/MSM.881925. PMID 21873960. 
  4. ↑ "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin 39 (4): 766–75. July 2013. doi:10.1093/schbul/sbt040. PMID 23512949. 
  5. ↑ "Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder". Molecular Psychiatry 1 (2): 121–4. May 1996. PMID 9118321. 
  6. ↑ "Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder". Molecular Psychiatry 3 (5): 427–30. September 1998. doi:10.1038/sj.mp.4000457. PMID 9774776. 
  7. ↑ "The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review". Pharmacology Biochemistry and Behavior 93 (3): 222–9. September 2009. doi:10.1016/j.pbb.2009.03.010. PMID 19336242. 
  8. ↑ "Genetics of impulse control disorders in Parkinson's disease". Journal of Neural Transmission 120 (4): 665–71. April 2013. doi:10.1007/s00702-012-0934-4. PMID 23232665. 
  9. ↑ "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. doi:10.1016/j.brainresrev.2009.10.007. PMID 19931559. 
  10. ↑ "Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development". Current Drug Targets 14 (4): 507–12. April 2013. doi:10.2174/1389450111314040012. PMID 23469923. 
  11. ↑ "Dopamine receptor signaling". Journal of Receptor and Signal Transduction Research 24 (3): 165–205. August 2004. doi:10.1081/RRS-200029981. PMID 15521361. 
  12. ↑ 12.0 12.1 "Multiple dopamine D4 receptor variants in the human population". Nature 358 (6382): 149–52. July 1992. doi:10.1038/358149a0. PMID 1319557. Bibcode: 1992Natur.358..149T. 
  13. ↑ "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. doi:10.1016/0006-3223(93)90236-7. PMID 8268330. 
  14. ↑ "The dopamine D4 receptor: biochemical and signalling properties". Cellular and Molecular Life Sciences 67 (12): 1971–86. June 2010. doi:10.1007/s00018-010-0293-y. PMID 20165900. 
  15. ↑ "Advances in genetic findings on attention deficit hyperactivity disorder". Psychological Medicine 37 (12): 1681–92. December 2007. doi:10.1017/S0033291707000773. PMID 17506925. 
  16. ↑ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 – SzGene database at Schizophrenia Research Forum.
  17. ↑ 17.0 17.1 "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biological Psychiatry 63 (2): 197–206. January 2008. doi:10.1016/j.biopsych.2007.04.006. PMID 17574217. 
  18. ↑ "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. doi:10.1016/j.ejphar.2007.01.055. PMID 17350612. 
  19. ↑ "Role of dopamine receptors in ADHD: a systematic meta-analysis". Molecular Neurobiology 45 (3): 605–20. June 2012. doi:10.1007/s12035-012-8278-5. PMID 22610946. 
  20. ↑ "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. doi:10.1176/appi.ajp.158.7.1052. PMID 11431226. 
  21. ↑ "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. doi:10.1016/s1388-2457(01)00524-7. PMID 11377270. 
  22. ↑ "DRD4 and DAT1 polymorphisms modulate human gamma band responses". Cerebral Cortex 17 (5): 1007–19. May 2007. doi:10.1093/cercor/bhl011. PMID 16751296. 
  23. ↑ 23.0 23.1 "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. doi:10.1086/420854. PMID 15077199. 
  24. ↑ "Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants". Journal of Neurochemistry 65 (3): 1157–65. September 1995. doi:10.1046/j.1471-4159.1995.65031157.x. PMID 7643093. 
  25. ↑ "Population Migration and the Variation of Dopamine D4 Receptor (DRD4) Allele Frequencies Around the Globe". Evolution and Human Behavior 20 (5): 309–24. 1999. doi:10.1016/S1090-5138(99)00015-X. http://www.escholarship.org/uc/item/7br14384. 
  26. ↑ "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. doi:10.1186/1471-2148-8-173. PMID 18544160. 
  27. ↑ "Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking". Nature Genetics 12 (1): 78–80. January 1996. doi:10.1038/ng0196-78. PMID 8528256. 
  28. ↑ "Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking". Nature Genetics 12 (1): 81–4. January 1996. doi:10.1038/ng0196-81. PMID 8528258. https://zenodo.org/record/1233375. 
  29. ↑ "Drd4 gene polymorphisms are associated with personality variation in a passerine bird". Proceedings: Biological Sciences 274 (1619): 1685–91. July 2007. doi:10.1098/rspb.2007.0337. PMID 17472912. 
  30. ↑ "Behaviour-related DRD4 polymorphisms in invasive bird populations". Molecular Ecology 23 (11): 2876–85. June 2014. doi:10.1111/mec.12763. PMID 24750181. 
  31. ↑ "Polymorphisms of the Dopamine D4 Receptor Gene in Stabled Horses are Related to Differences in Behavioral Response to Frustration". Animals 3 (3): 663–9. July 2013. doi:10.3390/ani3030663. PMID 26479526. 
  32. ↑ "Breed Differences in Dopamine Receptor D4 Gene (DRD4) in Horses". Journal of Equine Science 24 (3): 31–6. 2013. doi:10.1294/jes.24.31. PMID 24833999. 
  33. ↑ "Association of polymorphisms in the dopamine D4 receptor gene and the activity-impulsivity endophenotype in dogs". Animal Genetics 38 (6): 629–33. December 2007. doi:10.1111/j.1365-2052.2007.01657.x. PMID 17986156. 
  34. ↑ Timm, K.; Mägi, M.; Telva, K.; Tilgar, V. (2019). "The behavioural response of Great Tits to novel environment and handling is affected by the DRD4 gene". Ibis 161 (2): 91–100. doi:10.1111/ibi.12604. 
  35. ↑ 35.0 35.1 35.2 35.3 35.4 "Control networks and neuromodulators of early development". Developmental Psychology 48 (3): 827–35. May 2012. doi:10.1037/a0025530. PMID 21942663. 
  36. ↑ "Facilitatory effect of the dopamine D4 receptor agonist PD168,077 on memory consolidation of an inhibitory avoidance learned response in C57BL/6J mice". Behavioural Brain Research 142 (1–2): 41–52. June 2003. doi:10.1016/s0166-4328(02)00371-6. PMID 12798264. 
  37. ↑ "A-412997, a selective dopamine D4 agonist, improves cognitive performance in rats". Pharmacology Biochemistry and Behavior 82 (1): 148–55. September 2005. doi:10.1016/j.pbb.2005.08.002. PMID 16154186. 
  38. ↑ "Selective dopamine D4 receptor agonist (A-412997) improves cognitive performance and stimulates motor activity without influencing reward-related behaviour in rat". Behavioural Pharmacology 19 (8): 765–76. December 2008. doi:10.1097/FBP.0b013e32831c3b06. PMID 19020411. 
  39. ↑ "Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys". Psychopharmacology 142 (1): 78–84. February 1999. doi:10.1007/s002130050865. PMID 10102786. 
  40. ↑ "The selective dopamine D4 receptor antagonist, PNU-101387G, prevents stress-induced cognitive deficits in monkeys". Neuropsychopharmacology 23 (4): 405–10. October 2000. doi:10.1016/S0893-133X(00)00133-0. PMID 10989267. 
  41. ↑ "Neuronal correlates of ketamine and walking induced gamma oscillations in the medial prefrontal cortex and mediodorsal thalamus". PLOS ONE 12 (11): e0186732. 2017. doi:10.1371/journal.pone.0186732. PMID 29095852. Bibcode: 2017PLoSO..1286732F. 
  42. ↑ "Enhancement of gamma activity after selective activation of dopamine D4 receptors in freely moving rats and in a neurodevelopmental model of schizophrenia". Brain Structure & Function 219 (6): 2173–80. November 2014. doi:10.1007/s00429-013-0607-6. PMID 23839116. 
  43. ↑ "Behavioral and neurophysiological effects of Ro 10-5824, a dopamine D4 receptor partial agonist, in common marmosets". Psychopharmacology 232 (17): 3287–95. September 2015. doi:10.1007/s00213-015-3978-y. PMID 26041337. 
  44. ↑ "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology 188 (2): 244–51. October 2006. doi:10.1007/s00213-006-0490-4. PMID 16915381. 
  45. ↑ "A-412997 is a selective dopamine D4 receptor agonist in rats". Pharmacology Biochemistry and Behavior 82 (1): 140–7. September 2005. doi:10.1016/j.pbb.2005.08.001. PMID 16153699. 
  46. ↑ "Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction". Journal of Medicinal Chemistry 47 (15): 3853–64. July 2004. doi:10.1021/jm030505a. PMID 15239663. 
  47. ↑ "Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction". Journal of Medicinal Chemistry 49 (25): 7450–65. December 2006. doi:10.1021/jm060662k. PMID 17149874. 
  48. ↑ 48.0 48.1 "Cyanoindole derivatives as highly selective dopamine D(4) receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments". Journal of Medicinal Chemistry 43 (23): 4563–9. November 2000. doi:10.1021/jm0009989. PMID 11087581. 
  49. ↑ "1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction". Journal of Medicinal Chemistry 49 (17): 5093–109. August 2006. doi:10.1021/jm060279f. PMID 16913699. 
  50. ↑ "2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist". Journal of Medicinal Chemistry 49 (13): 3938–47. June 2006. doi:10.1021/jm060166w. PMID 16789750. 
  51. ↑ "2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist". Neuropharmacology 49 (1): 112–21. July 2005. doi:10.1016/j.neuropharm.2005.02.004. PMID 15992586. 
  52. ↑ 52.0 52.1 "Synthesis, radiofluorination, and in vitro evaluation of pyrazolo[1,5-a]pyridine-based dopamine D4 receptor ligands: discovery of an inverse agonist radioligand for PET". Journal of Medicinal Chemistry 51 (6): 1800–10. March 2008. doi:10.1021/jm701375u. PMID 18307287. 
  53. ↑ "3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor". Journal of Medicinal Chemistry 39 (10): 1941–2. May 1996. doi:10.1021/jm9600712. PMID 8642550. 
  54. ↑ "Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor". The Journal of Pharmacology and Experimental Therapeutics 283 (2): 636–47. November 1997. PMID 9353380. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9353380. 
  55. ↑ "Identification and pharmacological characterization of [125IL-750,667, a novel radioligand for the dopamine D4 receptor"]. Molecular Pharmacology 50 (6): 1658–64. December 1996. PMID 8967990. http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8967990. 
  56. ↑ "Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity". ACS Medicinal Chemistry Letters 5 (9): 1060–4. September 2014. doi:10.1021/ml500267c. PMID 25221667. 
  57. ↑ "S 18126 ([2-[4-(2,3-dihydrobenzo[1,4dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride"]. The Journal of Pharmacology and Experimental Therapeutics 287 (1): 167–86. October 1998. PMID 9765336. http://jpet.aspetjournals.org/cgi/content/abstract/287/1/167. 
  58. ↑ "Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine". Journal of Medicinal Chemistry 44 (8): 1151–7. April 2001. doi:10.1021/jm001055e. PMID 11312915. 

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