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.

  • Letter
  • Published:

Different binding epitopes on the NK1 receptor for substance P and a non-peptide antagonist

Nature volume 362, pages 345–348 (1993)Cite this article

Abstract

NON-PEPTIDE ligands for peptide receptors have been discovered in several systems through file screening programs1–6, but the mechanism of action for these candidate drugs is obscure as they do not chemically resemble the native peptides. The compound CP 96345 is a high-affinity, non-peptide antagonist of the substance P (NK1) receptor4,5,7, which is important in pain perception and neurogenic inflammation8–11. Here we identify epitopes on the NK1, receptor responsible for the specific binding of CP 96345 by systematic exchange of corresponding segments between the NK1, receptor and the homologous NK3 (neurokinin B) receptor, which does not bind the non-peptide ligand. Non-conserved residues, in two epitopes around the top of transmembrane segment V and in one epitope at the top of transmembrane segment VI, are essential for the specific action of CP 96345 on the NK1, receptor, but are surprisingly not important for the binding of the natural peptide ligand, substance P. Susceptibility to the non-peptide antagonists can be conveyed to the previously unresponsive NK3 receptor by mutational transfer of this discontinuous epitope from the NK1, receptor.

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

Similar content being viewed by others

References

  1. Freidinger, R. M. et al. in Neuropeptides and their Receptors (eds Schwartz, T. W., Hilsted, L. M & Rehfeld, J F.) 389–400 (Alfred Benzon Symposium 29, Munksgaard. Copenhagen, 1990).

    Google Scholar 

  2. Chang, R. S. L., & Lotti, V. J. Molec. Pharmac. 29, 347–351 (1989).

    Google Scholar 

  3. Dudley, D. T. et al. Molec. Pharmac. 38, 370–377 (1990).

    CAS  Google Scholar 

  4. Snider, R. M. et al. Science 251, 435–437 (1991).

    Article  ADS  CAS  Google Scholar 

  5. McLean, S. et al. Science 251, 437–439 (1991)

    Article  ADS  CAS  Google Scholar 

  6. Yamamura, Y. et al. Science 252, 572–574 (1991).

    Article  ADS  CAS  Google Scholar 

  7. Snider, R. M., Longo, K. P., Drozda, S. E., Lowe, III J. A. & Leeman, S. E. Proc. natn. Acad. Sci. U.S.A. 88, 10042–10044 (1991).

    Article  ADS  CAS  Google Scholar 

  8. Pernow, B. Pharmac. Rev. 35, 85–141 (1983).

    CAS  Google Scholar 

  9. Buck, S. H. & Burcher, E. Trend pharmac. Sci. 7, 65–68 (1986).

    Article  CAS  Google Scholar 

  10. McGillis, P., Mitsuyashi, M. & Payan, D. G. Ann. N Y. Acad Sci. 594, 85–94 (1990).

    Article  ADS  CAS  Google Scholar 

  11. Iversen, L. L., McKnight, A. T., Foster, A. C., Young, S. C. & Williams, B. J. in Neuropeptides and their Receptors (eds Schwartz, T. W., Histed, L. M. & Rehfeld, J. F.) 363–372 (Alfred Benzon Symposium 29, Munksgaard, Copenhagen, 1990).

    Google Scholar 

  12. Yokota, Y. et al. J. biol. Chem. 264, 17649–17652 (1989).

    Article  CAS  Google Scholar 

  13. Shigemoto, R., Yokota, Y., Tsuchida, K. & Nakanishi, S. J. biol. Chem. 265, 623–628 (1990).

    Article  CAS  Google Scholar 

  14. Engberg, G., Svensson, TI H., Rosell, S. & Folkers, K. Nature 293, 222–223 (1981).

    Article  ADS  CAS  Google Scholar 

  15. Mizrahi, J., Escher, E., D'Orleans-Juste, P. & Regoli, D. Eur. J. Pharmac. 99, 193–202 (1984).

    Article  CAS  Google Scholar 

  16. Laufer, R. et al. Proc. natn. Scad. Sci. U.S.A. 82, 7444–7448 (1985).

    Article  ADS  CAS  Google Scholar 

  17. Kobilka, B. K. et al. Science 240, 1310–1316 (1988).

    Article  ADS  CAS  Google Scholar 

  18. Dohlman, H. G., Thorner, J., Caron, M. G. & Lefkowitz, R. J. A. Rev. Biochem. 60, 653–688 (1991).

    Article  CAS  Google Scholar 

  19. Frielle, T., Daniel, K. W., Caron, M. G. & Lefkowitz, R. J. Proc. natn. Acad. Sci. U.S.A. 85, 9494–9498 (1988).

    Article  ADS  CAS  Google Scholar 

  20. Wess, J., Gdula, D. & Brann, M. R. Molec. Pharmac. 41, 369–374 (1992).

    CAS  Google Scholar 

  21. Dixon, R. A. F. et al. Nature 326, 73–77 (1987).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Wess, J., Gdula, D. & Brann, M. R. EMBO J. 10, 3729–3734 (1991).

    Article  CAS  Google Scholar 

  24. Johansen, T. E., Vogel, C. & Schwartz, T. W. Biochem. biophys. Res. Commun. 172, 1384–1391 (1990).

    Article  CAS  Google Scholar 

  25. Sanger, F., Nicklen, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).

    Article  ADS  CAS  Google Scholar 

  26. Johansen, T. E., Schøller, M. S., Tolstoy, S. & Schwartz, T. W. FEBS Lett. 267, 289–294 (1990).

    Article  CAS  Google Scholar 

  27. Gether, U., Marray, T., Schwartz, T. W. & Johansen, T. E. FEBS Lett. 296, 241–244 (1992).

    Article  CAS  Google Scholar 

  28. Fong, T. M., Huang, R. C. & Strader, C. D. J. biol. Chem. 267, 25664–25667 (1992).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Teit E. Johansen

    Present address: Johns Hopkins University, Department of Medicine, Bayview Circle, Baltimore, Maryland, 21224, USA

Authors and Affiliations

  1. Laboratory of Molecular Endocrinology, University Department of Clinical Biochemistry, Rigshospitalet 6321, Blegdamsvej 9, DK-Copenhagen, 2100, Denmark

    Ulrik Gether, Teit E. Johansen & Thue W. Schwartz

  2. Department of Exploratory Medicinal Chemistry, Central Research Division, Pfizer Inc., Groton, Connecticut, 06340, USA

    R. Michael Snider & John A. Lowe III

  3. Institute for Immunology, Faculty of Medicine, Kyoto University, Kyoto, 606, Japan

    Shigetada Nakanishi

Authors
  1. Ulrik Gether
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Teit E. Johansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Michael Snider
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John A. Lowe III
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shigetada Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thue W. Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gether, U., Johansen, T., Snider, R. et al. Different binding epitopes on the NK1 receptor for substance P and a non-peptide antagonist. Nature 362, 345–348 (1993). https://doi.org/10.1038/362345a0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/362345a0

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

Advanced 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