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Inhibition of protein kinase C by alcohols and anaesthetics

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Abstract

DESPITE almost a century of research, the mechanism of anaesthesia remains obscure and there is still no agreement on the location of the site(s) of action1–7. Because the potencies of general anaesthetics increase in proportion to their solubility in olive oil, this led to a consensus that the site is within the cell membrane8–10. This led to theories that lipid bilayer perturbation was the primary event, which was then transmitted to a membrane protein11. But at the concentrations used clinically, such perturbations are small3. A plausible site would be in or on ion channels at the synapse, where a number of modulatory effects have been described6. A possible location for such a site would be at the protein–lipid interface5,12,13. We report here that anaesthetics inhibit protein kinase C, a key component in signal transduction. The potency is a linear function of the octanol–water partition coefficient (the Meyer–Overton rule of anaesthesia). The effect was obtained in a lipid-free assay, implicating a hydrophobic site in the protein, supporting the contention that a (membrane) protein may be a target for anaesthetic interactions14–17. In a lipid-dependent assay, a potential role of lipids in the protein-site model was demonstrated. The inhibition was absent in the isolated catalytic domain, suggesting that the site of inhibition is on the regulatory subunit, which is unique to protein kinase C.

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Change history

  • 19 June 2018

    In the version of this Letter originally published, the author name was incorrectly stated as Mary Beth Keily rather than Mary Beth Kelly. This has been corrected.

References

  1. Seeman, P. Pharmac. Rev. 24, 583–639 (1972).

    CAS  Google Scholar 

  2. Haydon, D. A., Hendry, B. M., Levinson, S. R. & Requena, J. Nature 268, 356–358 (1977).

    Article  ADS  CAS  Google Scholar 

  3. Franks, N. P. & Lieb, W. R. Nature 300, 487–493 (1982).

    Article  ADS  CAS  Google Scholar 

  4. Dluzewski, A. R., Halsey, M. J. & Simmonds, A. C. Molec. Aspects Med. 6, 459–573 (1983).

    Article  CAS  Google Scholar 

  5. Miller, K. W. Int. Rev. Neurobiol. 27, 1–61 (1985).

    Article  ADS  CAS  Google Scholar 

  6. Rubin, E., Miller, K. W. & Roth, S. H. Ann. N.Y. Acad. Sci. 625 (1991).

  7. Matthews, R. Science 255, 156–157 (1992).

    Article  ADS  CAS  Google Scholar 

  8. Meyer, H. Arch exp. Path. Pharmak. 42, 109–118 (1889).

    Article  Google Scholar 

  9. Meyer, H. Arch exp. Path. Pharmak. 46, 338–346 (1901).

    Article  Google Scholar 

  10. Overton, E. Studien uber die Narkose (Fischer, Jena, 1901).

    Google Scholar 

  11. Richards, C. D. et al. Nature 276, 775–779 (1978).

    Article  ADS  CAS  Google Scholar 

  12. Fraser, D. M., Louro, S. R. W., Horvath, L. I., Miller, K. W. & Watts, A. Biochemistry 29, 2664–2669 (1990).

    Article  CAS  Google Scholar 

  13. Wood, S. C., Forman, S. A. & Miller, K. W. Molec. Pharmac. 39, 332–338 (1991).

    CAS  Google Scholar 

  14. Franks, N. P. & Lieb, W. R. Nature 310, 599–601 (1984).

    Article  ADS  CAS  Google Scholar 

  15. Franks, N. P. & Lieb, W. R. Nature 316, 349–351 (1985).

    Article  ADS  CAS  Google Scholar 

  16. Curry, S., Leib, W. R. & Franks, N. P. Biochemistry 29, 4641–4652 (1990).

    Article  CAS  Google Scholar 

  17. Moss, G. W. J., Franks, N. P. & Leib, W. R. Proc. natn. Acad. Sci. U.S.A. 88, 134–138 (1990).

    Article  ADS  Google Scholar 

  18. Bell, R. M. & Burns, D. J. J. biol. Chem. 266, 4661–4664 (1991).

    CAS  PubMed  Google Scholar 

  19. lnoue, M., Kishimoto, A., Takai, Y & Nishizuka, Y. J. biol. Chem. 252, 7610–7616 (1977).

    Google Scholar 

  20. Mikawa, K. et al. J. int. Med. Res. 18, 153–160 (1990).

    Article  CAS  Google Scholar 

  21. Trudell, J. R., Costa, A. K. & Hubbell, W. L. Ann. N.Y. Acad. Sci. 625, 743–746 (1991).

    Article  ADS  CAS  Google Scholar 

  22. Tas, P. W. & Koschel, K. Biochim. biophys. Acta 1091, 401–404 (1991).

    Article  CAS  Google Scholar 

  23. Alifimoff, J. K., Firestone, L. L. & Miller, K. W. Br. J. Pharmac. 96, 9–16 (1989).

    Article  CAS  Google Scholar 

  24. Trudell, J. R., Hubbell, W. L. & Cohen, E. N. Biochim. biophys. Acta 291, 321–327 (1973).

    Article  CAS  Google Scholar 

  25. Stubbs, C. D., Kinosita, K., Munkonge, F. M., Quinn, P. J. & Ikegami, A. Biochim. biophys. Acta 775, 374–380 (1984).

    Article  CAS  Google Scholar 

  26. Lee, M. & Bell, R. M. J. biol. Chem. 261, 14867–14870 (1986).

    CAS  PubMed  Google Scholar 

  27. Hanks, S. K., Quinn, A. M. & Hunter, T. Science 241, 42–52 (1992).

    Article  ADS  Google Scholar 

  28. Leo, A., Hansch, C. & Elkins, D. Chem. Rev. 71, 525–616 (1971).

    Article  CAS  Google Scholar 

  29. Kitano, T., Go M., Kikkawa, U. & Nishizuka, Y. Meth. Enzym. 124, 349–352 (1986).

    Article  CAS  Google Scholar 

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Slater, S., Cox, K., Lombardi, J. et al. Inhibition of protein kinase C by alcohols and anaesthetics. Nature 364, 82–84 (1993). https://doi.org/10.1038/364082a0

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