Dopamine receptor D4

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Dopamine receptor D4
Identifiers
SymbolsDRD4; D4DR
External IDsOMIM: 126452 MGI: 94926 HomoloGene: 20215 IUPHAR: D4 GeneCards: DRD4 Gene
RNA expression pattern
250px
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez181513491
EnsemblENSG00000069696ENSMUSG00000025496
UniProtP21917Q7TT80
RefSeq (mRNA)NM_000797NM_007878
RefSeq (protein)NP_000788NP_031904
Location (UCSC)Chr 11:
0.63 - 0.63 Mb		Chr 7:
141.14 - 141.15 Mb
PubMed search[1][2]

The dopamine receptor D4 is a G protein-coupled receptor encoded by the DRD4 gene.[1] As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions including schizophrenia, Parkinsons disease, bipolar disorder, addictive behaviors including sex addiction, and eating disorders such as anorexia nervosa, bulimia nervosa and binge eating. It is also a target for drugs which treat schizophrenia and Parkinson disease. 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.[2]

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:

  • A 48-base pair VNTR in exon 3
  • C-521T in the promotor
  • 13-base pair deletion of bases 235 to 247 in exon 1
  • 12 base pair repeat in exon I.[3]
  • Val194Gly
  • A polymorphic tandem duplication of 120 bp

Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder,[4] schizophrenia,[5] and the personality trait of novelty seeking.[6]

48-base pair VNTR

The 48-base pair VNTR in exon 3 range from 2 to 11 repeats. The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.[7] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats.

The 'DRD4 long' variant, or more specifically the 7 repeat (7R), has been loosely linked to a susceptibility for developing ADHD[8] and other psychological traits and disorders, like autism and bulimia nervosa[9]

7R appears to react less strongly to dopamine molecules.[10].

The 48 bp 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.[7]. In 1999 Chen and colleagues[11] 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.[12]

Novelty seeking

In two studies published in Nature Genetics,[13][14] subjects filled out personality questionnaires and had blood taken for genetic analysis. The scientists found that those whose answers showed them to be exploratory and excitable — two hallmarks of novelty-seeking — also possessed a longer 7 repeat (7R) version of D4DR, compared with those who are more reserved and reflective. A few other studies have replicated these results (including two done in Japan) but at least one has found no such correlation. In any case, thrill-seeking behavior is probably mediated by several genes, and the variance attributable to D4DR by itself is not particularly large.

A 2002 meta-analysis compared 22 published studies of novelty seeking and the polymorphism and found a so small effect that the meta-analysis could not support the relationship. Instead the pointed to another polymorphism in the gene: the -521C/T which seemed to have a small effect on novelty seeking.[15]

Ligands

File:D4 ligands.png
Chemical structures of representative D4-preferring ligands.

Agonists

  • WAY-100635: potent full agonist, with 5-HT1A antagonistic component[16]
  • A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels[17]
  • ABT-724 - developed for treatment of erectile dysfunction[18]
  • ABT-670 - better oral bioavailability than ABT-724[19]
  • FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes[20]
  • FAUC 299: partial agonist[20]
  • (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes[21]
  • PIP3EA: partial agonist[22]
  • 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

Antagonists

Inverse agonists

See also

References

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External links

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

Class A: Rhodopsin like
α1 (A, B, D) · α2 (A, B, C) · β1 · β2 · β3
Adenosine (A1, A2A, A2B, A3) · P2Y (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)
(all but 5-HT3) 5-HT1 (A, B, D, E, F) · 5-HT2 (A, B, C) · 5-HT (4, 5A, 6, 7)
Other
Acetylcholine (M1, M2, M3, M4, M5) · Dopamine (D1, D2, D3, D4, D5) · Histamine (H1, H2, H3, H4) · Melatonin (1A, 1B, 1C) · TAAR (1, 2, 3, 5, 6, 8, 9)
Metabolites and
signaling molecules
CysLT (1, 2) · LTB4 (1, 2) · FPRL1 · OXE · Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) · Prostacyclin · Thromboxane
Other
Bile acid · Cannabinoid (CB1, CB2, GPR (18, 55, 119)) · EBI2 · Estrogen · Free fatty acid (1, 2, 3, 4) · Lactate  · Lysophosphatidic acid (1, 2, 3, 4, 5, 6)  · Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) · Niacin (1, 2) · Oxoglutarate · PAF · Sphingosine-1-phosphate (1, 2, 3, 4, 5) · Succinate
Peptide
B/W (1, 2) · FF (1, 2) · S · Y (1, 2, 4, 5) · Neuromedin (B, U (1, 2)) · Neurotensin (1, 2)
Other
Miscellaneous
GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)
Other
Class B: Secretin like
GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)
Other
Class C: Metabotropic
glutamate / pheromone
TAS1R (1, 2, 3) · TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)
Other
Class F:
Frizzled / Smoothened
Frizzled
Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
Smoothened
pt:Receptor D4 de dopamina ru:Дофаминовый рецептор D4
  1. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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  5. ↑ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 - SzGene database at Schizophrenia Research Forum.
  6. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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  11. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. ↑ 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 Evol. Biol. 8: 173. doi:10.1186/1471-2148-8-173. PMC 2440754 Freely accessible. PMID 18544160. 
  13. ↑ 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. doi:10.1038/ng0196-78. PMID 8528256. 
  14. ↑ 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. doi:10.1038/ng0196-81. PMID 8528258. 
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  16. ↑ Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (2006). "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology (Berl.). 188 (2): 244–51. doi:10.1007/s00213-006-0490-4. PMID 16915381. 
  17. ↑ Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD (2005). "A-412997 is a selective dopamine D4 receptor agonist in rats". Pharmacol. Biochem. Behav. 82 (1): 140–7. doi:10.1016/j.pbb.2005.08.001. PMID 16153699. 
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  20. ↑ 20.0 20.1 Hübner H, Kraxner J, Gmeiner P (2000). "Cyanoindole derivatives as highly selective dopamine D4 receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments". J. Med. Chem. 43 (23): 4563–9. doi:10.1021/jm0009989. PMID 11087581. 
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  24. ↑ 24.0 24.1 Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P (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". J. Med. Chem. 51 (6): 1800. doi:10.1021/jm701375u. PMID 18307287. 
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  26. ↑ Patel S, Freedman S, Chapman KL; et al. (1 November 1997). "Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor". J. Pharmacol. Exp. Ther. 283 (2): 636–47. PMID 9353380. 
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  28. ↑ 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 (1 October 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". J. Pharmacol. Exp. Ther. 287 (1): 167–86. PMID 9765336. 
  29. ↑ Lanig H, Utz W, Gmeiner P (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". J. Med. Chem. 44 (8): 1151–7. doi:10.1021/jm001055e. PMID 11312915. 
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