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.

Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine

Abstract

DOPAMINE receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1,D2,D3) have been cloned1–7. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia8,9. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine10 is one of the most favoured antipsychotics because it does not cause tardive dyskinesia11. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water12,13. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Bunzow, J. R. et al. Nature 336, 783–787 (1988).

    Article  ADS  CAS  Google Scholar 

  2. Grandy, D. K. et al. Proc. natn. Acad. Sci. U.S.A. 86, 9762–9766 (1989).

    Article  ADS  CAS  Google Scholar 

  3. Dal Toso, R. et al. EMBO J. 8, 4025–4034 (1989).

    Article  CAS  Google Scholar 

  4. Zhou, Q-Y. et al. Nature 347, 76–80 (1990).

    Article  ADS  CAS  Google Scholar 

  5. Sunahara, R. K. et al. Nature 347, 80–83 (1990).

    Article  ADS  CAS  Google Scholar 

  6. Dearry, A. et al. Nature 347, 72–76 (1990).

    Article  ADS  CAS  Google Scholar 

  7. Sokoloff, P., Giros, B., Martres, M.-P., Bouthenet, M.-L. & Schwartz, J.-C. Nature 347, 146–151 (1990).

    Article  ADS  CAS  Google Scholar 

  8. Seeman, P. et al. Neuropsychopharmacology 1, 5–15 (1987).

    Article  CAS  Google Scholar 

  9. Seeman, P. Synapse 1, 152–333 (1987).

    Google Scholar 

  10. Kane, J. et al. Arch. Gen. Psychiat. 45, 789–796 (1988).

    Article  CAS  Google Scholar 

  11. Casey, D. E. Psychopharmacology 99, S47–S53 (1989).

    Article  Google Scholar 

  12. Ackenheil, M., Brau, H., Burkhart, A., Franke, A. & Pacha, W. Arzneimlttel Forsch. 26, 1156–1158 (1976).

    CAS  Google Scholar 

  13. Clozaril: Summary of Preclinical and Clinical Data (Sandoz Canada. Inc., 1990).

  14. Kozak, M. Nucleic Acids Res. 12, 857–872 (1984).

    Article  CAS  Google Scholar 

  15. Mount, S. M. Nucleic Acids Res. 10, 461–472 (1982).

    Article  Google Scholar 

  16. Dohlman, H. G., Caron, M. G. & Lefkowitz, R. J. Biochemistry 26, 2657–2664 (1987).

    Article  CAS  Google Scholar 

  17. Hubbard, S. & Ivatt, R. A. Rev. Biochem. 50, 555–583 (1981).

    Article  CAS  Google Scholar 

  18. Strader, C. D. et al. J. biol. Chem. 263, 10267–10271 (1988).

    CAS  PubMed  Google Scholar 

  19. Strader, C. D., Candelore, M. R., Hill, W. S., Sigal, I. S. & Dixon, R. A. F. J. biol. Chem. 264, 13572–13578 (1989).

    CAS  PubMed  Google Scholar 

  20. Sibley, D. R., Benovic, J. L., Caron, M. G. & Lefkowitz, R. J. Cell 48, 913–922 (1987).

    Article  CAS  Google Scholar 

  21. Bouvier, M. et al. Nature 333, 370–373 (1988).

    Article  ADS  CAS  Google Scholar 

  22. O'Dowd, B. F., Hnatowich, M., Caron, M. G., Lefkowitz, R. J. & Bouvier, M. J. biol. Chem. 264, 7564–7569 (1989).

    CAS  PubMed  Google Scholar 

  23. Bonner, T. I., Young, A., Brann, M. R. & Buckley, N. J. Neuron 1, 403–410 (1988).

    Article  CAS  Google Scholar 

  24. Chen, C. & Okayama, H. Molec. cell. Biol. 7, 2745–2752 (1987).

    Article  CAS  Google Scholar 

  25. Hamer, D. J. & Leder, P. L. Cell 18, 1299–1302 (1979).

    Article  CAS  Google Scholar 

  26. Gray, P. W. & Goedell, D. V. Proc. natn. Acad. Sci. U.S.A. 80, 5842–5846 (1983).

    Article  ADS  CAS  Google Scholar 

  27. Seeman, P. Acta psychiatr. scand. 82, (Suppl. 358), 14–20 (1990).

    Article  Google Scholar 

  28. Seeman, P. & Niznik, H. B. ISI Atlas Sci. Pharmac. 2, 161–170 (1988).

    CAS  Google Scholar 

  29. Seeman, P. et al. Eur. J. Pharmac. 56, 247–251 (1979).

    Article  CAS  Google Scholar 

  30. Stormann, T. M., Gdula, D. C., Weiner, D. M. & Brann, M. R. Molec. Pharmac. 37, 1–6 (1990).

    CAS  Google Scholar 

  31. Giros, B. et al. Nature 342, 923–926 (1989).

    Article  ADS  CAS  Google Scholar 

  32. Sanchez-Roa, P. M. et al. Life Sci. 45, 1821–1829 (1989).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Van Tol, H., Bunzow, J., Guan, HC. et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350, 610–614 (1991). https://doi.org/10.1038/350610a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/350610a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing