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Induction of vanilloid receptor channel activity by protein kinase C

Nature volume 408, pages 985–990 (2000)Cite this article

Abstract

Capsaicin or vanilloid receptors (VRs) participate in the sensation of thermal and inflammatory pain1,2,3. The cloned (VR1) and native VRs are non-selective cation channels directly activated by harmful heat, extracellular protons and vanilloid compounds4,5,6,7,8. However, considerable attention has been focused on identifying other signalling pathways in VR activation; it is known that VR1 is also expressed in non-sensory tissue1,9 and may mediate inflammatory rather than acute thermal pain3. Here we show that activation of protein kinase C (PKC) induces VR1 channel activity at room temperature in the absence of any other agonist. We also observed this effect in native VRs from sensory neurons, and phorbol esters induced a vanilloid-sensitive Ca2+ rise in these cells. Moreover, the pro-inflammatory peptide, bradykinin, and the putative endogenous ligand, anandamide, respectively induced and enhanced VR activity, in a PKC-dependent manner. These results suggest that PKC may link a range of stimuli to the activation of VRs.

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Figure 1: Phorbol ester activates VR1-mediated currents in oocytes.
Figure 2: TPA and ATPγs induce single channel VR1 activity.
Figure 3: TPA induces VR channel activity and a calcium rise in DRG neurons.
Figure 4: Bradykinin activates VRs via PKC.
Figure 5: Enhancement of anandamide-evoked VR1 responses via PKC.

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References

  1. Szallasi, A. & Blumberg, P. M. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol. Rev. 51, 159–212 (1999).

    CAS  PubMed  Google Scholar 

  2. Caterina, M. J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Davis, J. B. et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405, 183–187 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Wood, J. N. et al. Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J. Neurosci. 8, 3208–3220 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dray, A., Forbes, C. A. & Burgess, G. M. Ruthenium red blocks the capsaicin-induced increase in intracellular calcium and activation of membrane currents in sensory neurones as well as the activation of peripheral nociceptors in vitro. Neurosci. Lett. 110, 52–59 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. Oh, U., Hwang, S. W. & Kim, D. Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons. J. Neurosci. 16, 1659–1667 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Tominaga, M. et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Mezey, E. et al. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc. Natl Acad. Sci. USA 97, 3655–3660 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khasar, S. G. et al. A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice. Neuron 24, 253–260 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Cesare, P. & McNaughton, P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc. Natl Acad. Sci. USA 93, 15435–15439 (1996).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cesare, P., Dekker, L. V., Sardini, A., Parker, P. J. & McNaughton, P. A. Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Neuron 23, 617–624 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Mizumura, K., Koda, H. & Kumazawa, T. Evidence that protein kinase C activation is involved in the excitatory and facilitatory effects of bradykinin on canine visceral nociceptors in vitro. Neurosci. Lett. 237, 29–32 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Dunn, P. M. & Rang, H. P. Bradykinin-induced depolarization of primary afferent nerve terminals in the neonatal rat spinal cord in vitro. Br. J. Pharmacol. 100, 656–660 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Burgess, G. M., Mullaney, I., McNeill, M., Dunn, P. M. & Rang, H. P. Second messengers involved in the mechanism of action of bradykinin in sensory neurons in culture. J. Neurosci. 9, 3314–3325 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dray, A., Bettaney, J., Forster, P. & Perkins, M. N. Bradykinin-induced stimulation of afferent fibres is mediated through protein kinase C. Neurosci. Lett. 91, 301–307 (1988).

    Article  CAS  PubMed  Google Scholar 

  17. Barber, L. A. & Vasko, M. R. Activation of protein kinase C augments peptide release from rat sensory neurons. J. Neurochem. 67, 72–80 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Frayer, S. M., Barber, L. A. & Vasko, M. R. Activation of protein kinase C enhances peptide release from rat spinal cord slices. Neurosci. Lett. 265, 17–20 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Kessler, F., Habelt, C., Averbeck, B., Reeh, P. W. & Kress, M. Heat-induced release of CGRP from isolated rat skin and effects of bradykinin and the protein kinase C activator PMA. Pain 83, 289–295 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Toullec, D. et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J. Biol. Chem. 266, 15771–15781 (1991)

    CAS  PubMed  Google Scholar 

  21. Docherty, R. J., Yeats, J. C., Bevan, S. & Boddeke, H. W. Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats. Pflugers Arch. 431, 828–837 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Zygmunt, P. M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Smart, D. et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J. Pharmacol. 129, 227–230 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. De Petrocellis, L., Orlando, P. & Di Marzo, V. Anandamide, an endogenous cannabinomimetic substance, modulates rat brain protein kinase C in vitro. Biochem. Mol. Biol. Int. 36, 1127–1133 (1995).

    CAS  PubMed  Google Scholar 

  25. Hwang, S. W. et al. Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances. Proc. Natl Acad. Sci. USA 97, 6155–6160 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Methfessel, C. et al. Patch clamp measurement on Xenopus laevis oocyte: current through endogenous channels and implanted acetylcholine receptor and sodium channels. Pflugers Arch 407, 577–588 (1986).

    Article  CAS  PubMed  Google Scholar 

  27. Brewer, G. J., Torricelli, J. R., Evege, E. K. & Price, P. J. Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination. J. Neurosci. Res. 35, 567–576 (1993).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank D. Hallam for assistance with the culture of DRG neurons, and M. Caterina and D. Julius for the gift of VR1. This work was supported by the NSF.

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  1. Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, 62702, Illinois, USA

    Louis S. Premkumar & Gerard P. Ahern

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  1. Louis S. Premkumar
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  2. Gerard P. Ahern
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Correspondence to Louis S. Premkumar.

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Premkumar, L., Ahern, G. Induction of vanilloid receptor channel activity by protein kinase C. Nature 408, 985–990 (2000). https://doi.org/10.1038/35050121

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