Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The human dopamine D4 receptor repeat sequences modulate expression

The Pharmacogenomics Journal volume 3, pages 343–348 (2003)Cite this article

ABSTRACT

Genetic studies have implicated a polymorphic repeat sequence in exon 3 of the human dopamine D4 receptor in various behavioral and psychiatric disorders. Functionally various repeat variants are nearly identical, but whether these have different effects on gene expression has not been studied. To study the role of the repeat sequences on expression independently from its structural and functional effects at the protein level, we introduced these sequences immediately upstream of the promoter and in the 3′ untranslated region of a luciferase reporter vector. In this report, we demonstrate that the repeat sequence can both modulate promoter activity and alter expression post-transcriptionally. The repeat sequence can serve as a substrate for a nuclear binding factor and all the three repeat variants can suppress promoter activity. Placement of the three repeat variants downstream from the luciferase gene in the expression vector shows, however, that the D4.7 repeat sequence has significantly suppressed expression of the reporter compared to the D4.2 and D4.4 repeats, likely via mechanisms involving RNA stability or translational efficiency. These data indicate that the various D4 repeat sequences have different effects on expression, which may explain its potential role in behavioral disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Oak JN, Oldenhof J, Van Tol HH . The dopamine D4 receptor: one decade of research. Eur J Pharmacol 2000; 405: 303–327.

    Article  CAS  Google Scholar 

  2. Helmeste DM, Tang SW . Dopamine D4 receptors. Jpn J Pharmacol 2000; 82: 1–14.

    Article  CAS  Google Scholar 

  3. Wong AH, Buckle CE, Van Tol HH . Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 2000; 410: 183–203.

    Article  CAS  Google Scholar 

  4. Ding YC, Chi HC, Grady DL, Morishima A, Kidd JR, Kidd KK et al. Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci USA 2002; 99: 309–314.

    Article  CAS  Google Scholar 

  5. Lichter JB, Barr CL, Kennedy JL, Van Tol HH, Kidd KK, Livak KJ . A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum Mol Genet 1993; 2: 767–773.

    Article  CAS  Google Scholar 

  6. Asghari V, Schoots O, van Kats S, Ohara K, Jovanovic V, Guan HC et al. Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes. Mol Pharmacol 1994; 46: 364–373.

    CAS  PubMed  Google Scholar 

  7. Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK . The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Hum Genet 1996; 98: 91–101.

    Article  CAS  Google Scholar 

  8. Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O et al. Multiple dopamine D4 receptor variants in the human population. Nature 1992; 358: 149–152.

    Article  CAS  Google Scholar 

  9. 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. Am J Psychiatry 2001; 158: 1052–1057.

    Article  CAS  Google Scholar 

  10. LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N et al. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry 1996; 1: 121–124.

    CAS  PubMed  Google Scholar 

  11. Swanson J, Oosterlaan J, Murias M, Schuck S, Flodman P, Spence MA et al. Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention. Proc Natl Acad Sci USA 2000; 97: 4754–4759.

    Article  CAS  Google Scholar 

  12. Kazmi MA, Snyder LA, Cypess AM, Graber SG, Sakmar TP . Selective reconstitution of human D4 dopamine receptor variants with Gi alpha subtypes. Biochemistry 2000; 39: 3734–3744.

    Article  CAS  Google Scholar 

  13. Jovanovic V, Guan HC, Van Tol HH . Comparative pharmacological and functional analysis of the human dopamine D4.2 and D4.10 receptor variants. Pharmacogenetics 1999; 9: 561–568.

    Article  CAS  Google Scholar 

  14. Falzone TL, Gelman DM, Young JI, Grandy DK, Low MJ, Rubinstein M . Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear. Eur J Neurosci 2002; 15: 158–164.

    Article  Google Scholar 

  15. Dulawa SC, Grandy DK, Low MJ, Paulus MP, Geyer MA . Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci 1999; 19: 9550–9556.

    Article  CAS  Google Scholar 

  16. Cohen AI, Todd RD, Harmon S, O'Malley KL . Photoreceptors of mouse retinas possess D4 receptors coupled to adenylate cyclase. Proc Natl Acad Sci USA 1992; 89: 12093–12097.

    Article  CAS  Google Scholar 

  17. Nir I, Harrison JM, Haque R, Low MJ, Grandy DK, Rubinstein M et al. Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. J Neurosci 2002; 22: 2063–2073.

    Article  CAS  Google Scholar 

  18. Wang X, Zhong P, Yan Z . Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. J Neurosci 2002; 22: 9185–9193.

    Article  CAS  Google Scholar 

  19. Kotecha SA, Oak JN, Jackson MF, Perez Y, Orser BA, Van Tol HH et al. A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron 2002; 35: 1111–1122.

    Article  CAS  Google Scholar 

  20. Arnsten AF, Murphy B, Merchant K . The selective dopamine D4 receptor antagonist, PNU-101387G, prevents stress-induced cognitive deficits in monkeys. Neuropsychopharmacology 2000; 23: 405–410.

    Article  CAS  Google Scholar 

  21. Jentsch JD, Taylor JR, Redmond Jr DE, Elsworth JD, Youngren KD, Roth RH . Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys. Psychopharmacology (Berl) 1999; 142: 78–84.

    Article  CAS  Google Scholar 

  22. 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. J Neurochem 1995; 65: 1157–1165.

    Article  CAS  Google Scholar 

  23. Ghosh D . Object-oriented transcription factors database (ooTFD). Nucleic Acids Res 2000; 28: 308–310.

    Article  CAS  Google Scholar 

  24. Sanyal S, Van Tol HH . Dopamine D4 receptor-mediated inhibition of cyclic adenosine 3′,5′-monophosphate production does not affect prolactin regulation. Endocrinology 1997; 138: 1871–1878.

    Article  CAS  Google Scholar 

  25. Knapp M, Wong AH, Schoots O, Guan HC, Van Tol HH . Promoter-independent regulation of cell-specific dopamine receptor expression. FEBS Lett 1998; 434: 108–114.

    Article  CAS  Google Scholar 

  26. Makeyev AV, Liebhaber SA . The poly(C)-binding proteins: a multiplicity of functions and a search for mechanisms. RNA 2002; 8: 265–278.

    Article  CAS  Google Scholar 

  27. Dalphin ME, Stockwell PA, Tate WP, Brown CM . TransTerm, the translational signal database, extended to include full coding sequences and untranslated regions. Nucleic Acids Res 1999; 27: 293–294.

    Article  CAS  Google Scholar 

  28. Ostareck-Lederer A, Ostareck DH, Standart N, Thiele BJ . Translation of 15-lipoxygenase mRNA is inhibited by a protein that binds to a repeated sequence in the 3′ untranslated region. EMBO J 1994; 13: 1476–1481.

    Article  CAS  Google Scholar 

  29. Reimann I, Huth A, Thiele H, Thiele BJ . Suppression of 15-lipoxygenase synthesis by hnRNP E1 is dependent on repetitive nature of LOX mRNA 3′-UTR control element DICE. J Mol Biol 2002; 315: 965–974.

    Article  CAS  Google Scholar 

  30. Dignam JD, Lebovitz RM, Roeder RG . Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 1983; 11: 1475–1489.

    Article  CAS  Google Scholar 

  31. de Wet JR, Wood KV, DeLuca M, Helinski DR, Subramani S . Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol 1987; 7: 725–737.

    Article  CAS  Google Scholar 

  32. Schoots O, Voskoglou T, Van Tol HH . Genomic organization and promoter analysis of the human G-protein-coupled K+ channel Kir3.1 (KCNJ3/HGIRK1). Genomics 1997; 39: 279–288.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Mrs V Jovanovic for expert assistance in various experiments, and Drs Albert Wong and Kathleen van Craenenbroeck for editing the manuscript. The work is supported by the Canadian Institutes of Health Research. HHMVT holds a Canada Research Chair in Neurobiology.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Neurobiology, Centre for Addiction & Mental Health,

    O Schoots & H H M Van Tol

  2. Departments of Psychiatry, Pharmacology, Ontario, Canada

    O Schoots & H H M Van Tol

Authors
  1. O Schoots
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H H M Van Tol
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H H M Van Tol.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schoots, O., Van Tol, H. The human dopamine D4 receptor repeat sequences modulate expression. Pharmacogenomics J 3, 343–348 (2003). https://doi.org/10.1038/sj.tpj.6500208

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500208

Keywords

This article is cited by

Search

Advanced search

Quick links