Dopamine receptor D4

DRD4
Identifiers
AliasesDRD4, D4DR, dopamine receptor D4
External IDsMGI: 94926 HomoloGene: 20215 GeneCards: DRD4
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

1815

13491

Ensembl

ENSG00000069696
ENSG00000276825

ENSMUSG00000025496

UniProt

P21917

P51436

RefSeq (mRNA)

NM_000797

NM_007878

RefSeq (protein)

NP_000788

NP_031904

Location (UCSC)Chr 11: 0.64 – 0.64 MbChr 7: 141.29 – 141.3 Mb
PubMed search[1][2]
Wikidata
View/Edit HumanView/Edit Mouse

The dopamine receptor D4 is a G protein-coupled receptor encoded by the DRD4 gene.[3]

As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions[4] including schizophrenia and bipolar disorder,[5] ADHD,[6][7] addictive behaviors,[8] Parkinson's disease,[9] and eating disorders such as anorexia nervosa.[10]

It is also a target for drugs which treat schizophrenia and Parkinson disease.[11] 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.[12]

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:

Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder,[14] schizophrenia[15] and the personality trait of novelty seeking.[16]


48-base pair VNTR

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

DRD4-7R, the 7-repeat (7R) variant of DRD4, has been linked to a susceptibility for developing ADHD in several meta-analyses and other psychological traits and disorders.[17][18]

The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.[19] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.[20]

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.[19] In 1999 Chen and colleagues[21] 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.[22]

Novelty seeking

Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a normal characteristic of exploratory and excitable people),[23][24] 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.[16] While human results are controversial, an increasing body of animal evidence has linked DRD4 variants with novelty seeking,[25][26][27][28][29] and new evidence suggests that human encroachment may exert selection pressure in favor of DRD4 variants associated with novelty seeking.[30] 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.[30] 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.[30] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.[30] Higher quality parenting was associated with better executive control in 4-year-olds.[30]

Ligands

Chemical structures of representative D4-preferring ligands.

Agonists

Antagonists

Inverse agonists

See also

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991). "Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine". Nature. 350 (6319): 610–4. PMID 1840645. doi:10.1038/350610a0.
  4. ↑ Ptácek R, Kuzelová H, Stefano GB (2011). "Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders". Medical Science Monitor. 17 (9): RA215–20. PMC 3560519 Freely accessible. PMID 21873960. doi:10.12659/MSM.881925.
  5. ↑ Domschke K (2013). "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin. 39 (4): 766–75. PMC 3686457 Freely accessible. PMID 23512949. doi:10.1093/schbul/sbt040.
  6. ↑ GJ, LaHoste; JM, Swanson; SB, Wigal; C, Glabe; T, Wigal; N, King; JL, Kennedy (1996-05-01). "Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder.". Molecular Psychiatry. 1 (2): 121–4. ISSN 1359-4184. PMID 9118321.
  7. ↑ Smalley, S L; Bailey, J N; Palmer, C G; Cantwell, D P; McGough, J J; Del’Homme, M A; Asarnow, J R; Woodward, J A; Ramsey, C (1998-09-01). "Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder". Molecular Psychiatry. 3 (5): 427–430. ISSN 1359-4184. PMID 9774776. doi:10.1038/sj.mp.4000457.
  8. ↑ McGeary J (2009). "The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review". Pharmacology, Biochemistry, and Behavior. 93 (3): 222–9. PMC 2706302 Freely accessible. PMID 19336242. doi:10.1016/j.pbb.2009.03.010.
  9. ↑ Cormier F, Muellner J, Corvol JC (2013). "Genetics of impulse control disorders in Parkinson's disease". Journal of Neural Transmission. 120 (4): 665–71. PMID 23232665. doi:10.1007/s00702-012-0934-4.
  10. ↑ Rask-Andersen M, Olszewski PK, Levine AS, Schiöth HB (2010). "Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake". Brain Research Reviews. 62 (2): 147–64. PMID 19931559. doi:10.1016/j.brainresrev.2009.10.007.
  11. ↑ Ptáček R, Kuželová H, Stefano GB, Raboch J, Kream RM (2013). "Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development". Current Drug Targets. 14 (4): 507–12. PMID 23469923. doi:10.2174/1389450111314040012.
  12. ↑ Neve KA, Seamans JK, Trantham-Davidson H (2004). "Dopamine receptor signaling". Journal of Receptor and Signal Transduction Research. 24 (3): 165–205. PMID 15521361. doi:10.1081/RRS-200029981.
  13. ↑ Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E (1993). "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. PMID 8268330. doi:10.1016/0006-3223(93)90236-7.
  14. ↑ Thapar A, Langley K, Owen MJ, O'Donovan MC (2007). "Advances in genetic findings on attention deficit hyperactivity disorder". Psychological Medicine. 37 (12): 1681–92. PMID 17506925. doi:10.1017/S0033291707000773.
  15. ↑ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 - SzGene database at Schizophrenia Research Forum.
  16. 1 2 Munafò MR, Yalcin B, Willis-Owen SA, Flint J (2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biological Psychiatry. 63 (2): 197–206. PMID 17574217. doi:10.1016/j.biopsych.2007.04.006.
  17. ↑ Wu J, Xiao H, Sun H, Zou L, Zhu LQ (2012). "Role of dopamine receptors in ADHD: a systematic meta-analysis". Molecular Neurobiology. 45 (3): 605–20. PMID 22610946. doi:10.1007/s12035-012-8278-5.
  18. ↑ Faraone SV, Doyle AE, Mick E, Biederman J (2001). "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. PMID 11431226. doi:10.1176/appi.ajp.158.7.1052.
  19. 1 2 Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK (2004). "The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus". American Journal of Human Genetics. 74 (5): 931–44. PMC 1181986 Freely accessible. PMID 15077199. doi:10.1086/420854.
  20. ↑ Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (1995). "Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants". Journal of Neurochemistry. 65 (3): 1157–65. PMID 7643093. doi:10.1046/j.1471-4159.1995.65031157.x.
  21. ↑ Chen CS, Burton M, Greenberger E, Dmitrieva J (1999). "Population Migration and the Variation of Dopamine D4 Receptor (DRD4) Allele Frequencies Around the Globe". Evolution and Human Behavior. 20 (5): 309–24. doi:10.1016/S1090-5138(99)00015-X.
  22. ↑ Eisenberg DT, Campbell B, Gray PB, Sorenson MD (2008). "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. PMC 2440754 Freely accessible. PMID 18544160. doi:10.1186/1471-2148-8-173.
  23. ↑ Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH (1996). "Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking". Nature Genetics. 12 (1): 78–80. PMID 8528256. doi:10.1038/ng0196-78.
  24. ↑ Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (1996). "Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking". Nature Genetics. 12 (1): 81–4. PMID 8528258. doi:10.1038/ng0196-81.
  25. ↑ Fidler AE, van Oers K, Drent PJ, Kuhn S, Mueller JC, Kempenaers B (2007). "Drd4 gene polymorphisms are associated with personality variation in a passerine bird". Proceedings of the Royal Society B: Biological Sciences. 274 (1619): 1685–91. PMC 1914334 Freely accessible. PMID 17472912. doi:10.1098/rspb.2007.0337.
  26. ↑ Mueller JC, Edelaar P, Carrete M, Serrano D, Potti J, Blas J, Dingemanse NJ, Kempenaers B, Tella JL (2014). "Behaviour-related DRD4 polymorphisms in invasive bird populations". Molecular Ecology. 23 (11): 2876–85. PMID 24750181. doi:10.1111/mec.12763.
  27. ↑ Ninomiya S, Anjiki A, Nishide Y, Mori M, Deguchi Y, Satoh T (2013). "Polymorphisms of the Dopamine D4 Receptor Gene in Stabled Horses are Related to Differences in Behavioral Response to Frustration". Animals. 3 (3): 663–9. PMC 4494454 Freely accessible. PMID 26479526. doi:10.3390/ani3030663.
  28. ↑ Hori Y, Ozaki T, Yamada Y, Tozaki T, Kim HS, Takimoto A, Endo M, Manabe N, Inoue-Murayama M, Fujita K (2013). "Breed Differences in Dopamine Receptor D4 Gene (DRD4) in Horses". Journal of Equine Science. 24 (3): 31–6. PMC 4013985 Freely accessible. PMID 24833999. doi:10.1294/jes.24.31.
  29. ↑ Hejjas K, Vas J, Topal J, Szantai E, Ronai Z, Szekely A, Kubinyi E, Horvath Z, Sasvari-Szekely M, Miklosi A (2007). "Association of polymorphisms in the dopamine D4 receptor gene and the activity-impulsivity endophenotype in dogs". Animal Genetics. 38 (6): 629–33. PMID 17986156. doi:10.1111/j.1365-2052.2007.01657.x.
  30. 1 2 3 4 5 Posner MI, Rothbart MK, Sheese BE, Voelker P (2012). "Control networks and neuromodulators of early development". Developmental Psychology. 48 (3): 827–35. PMC 3253251 Freely accessible. PMID 21942663. doi:10.1037/a0025530.
  31. ↑ Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (Oct 2006). "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology. 188 (2): 244–51. PMID 16915381. doi:10.1007/s00213-006-0490-4.
  32. ↑ Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD (Sep 2005). "A-412997 is a selective dopamine D4 receptor agonist in rats". Pharmacology, Biochemistry, and Behavior. 82 (1): 140–7. PMID 16153699. doi:10.1016/j.pbb.2005.08.001.
  33. ↑ Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO (Jul 2004). "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. PMID 15239663. doi:10.1021/jm030505a.
  34. ↑ Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO (Dec 2006). "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. PMID 17149874. doi:10.1021/jm060662k.
  35. 1 2 Hübner H, Kraxner J, Gmeiner P (Nov 2000). "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. PMID 11087581. doi:10.1021/jm0009989.
  36. ↑ Kolasa T, Matulenko MA, Hakeem AA, Patel MV, Mortell K, Bhatia P, Henry R, Nakane M, Hsieh GC, Terranova MA, Uchic ME, Miller LN, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino B, El Kouhen O, Marsh KC, Wetter JM, Moreland RB, Brioni JD, Stewart AO (Aug 2006). "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. PMID 16913699. doi:10.1021/jm060279f.
  37. ↑ Enguehard-Gueiffier C, Hübner H, El Hakmaoui A, Allouchi H, Gmeiner P, Argiolas A, Melis MR, Gueiffier A (Jun 2006). "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. PMID 16789750. doi:10.1021/jm060166w.
  38. ↑ Nakane M, Cowart MD, Hsieh GC, Miller L, Uchic ME, Chang R, Terranova MA, Donnelly-Roberts DL, Namovic MT, Miller TR, Wetter JM, Marsh K, Stewart AO, Brioni JD, Moreland RB (Jul 2005). "2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist". Neuropharmacology. 49 (1): 112–21. PMID 15992586. doi:10.1016/j.neuropharm.2005.02.004.
  39. 1 2 Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P (Mar 2008). "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. PMID 18307287. doi:10.1021/jm701375u.
  40. ↑ Kulagowski JJ, Broughton HB, Curtis NR, Mawer IM, Ridgill MP, Baker R, Emms F, Freedman SB, Marwood R, Patel S, Patel S, Ragan CI, Leeson PD (May 1996). "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. PMID 8642550. doi:10.1021/jm9600712.
  41. ↑ Patel S, Freedman S, Chapman KL, Emms F, Fletcher AE, Knowles M, Marwood R, Mcallister G, Myers J, Curtis N, Kulagowski JJ, Leeson PD, Ridgill M, Graham M, Matheson S, Rathbone D, Watt AP, Bristow LJ, Rupniak NM, Baskin E, Lynch JJ, Ragan CI (Nov 1997). "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. PMID 9353380.
  42. ↑ Patel S, Patel S, Marwood R, Emms F, Marston D, Leeson PD, Curtis NR, Kulagowski JJ, Freedman SB (Dec 1996). "Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor". Molecular Pharmacology. 50 (6): 1658–64. PMID 8967990.
  43. ↑ Berry CB, Bubser M, Jones CK, Hayes JP, Wepy JA, Locuson CW, Daniels JS, Lindsley CW, Hopkins CR (2014). "Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity". ACS Med Chem Lett. 5 (9): 1060–4. PMC 4160761 Freely accessible. PMID 25221667. doi:10.1021/ml500267c.
  44. ↑ Millan MJ, Newman-Tancredi A, Brocco M, Gobert A, Lejeune F, Audinot V, Rivet JM, Schreiber R, Dekeyne A, Spedding M, Nicolas JP, Peglion JL (Oct 1998). "S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-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. PMID 9765336.
  45. ↑ Lanig H, Utz W, Gmeiner P (Apr 2001). "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. PMID 11312915. doi:10.1021/jm001055e.

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