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The capsaicin receptor: a heat-activated ion channel in the pain pathway

Abstract

Capsaicin, the main pungent ingredient in ‘hot’ chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.

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Figure 1: Expression cloning of a capsaicin receptor using calcium imaging.
Figure 2: VR1 responds to purified vanilloids and pepper extracts.
Figure 3: VR1 responds to purified vanilloids and pepper extracts.
Figure 4: VR1 is a calcium-permeable, non-selective cation channel.
Figure 5: Capsaicin induces death of cells expressing the vanilloid receptor.
Figure 6: VR1 resembles store-operated channels.
Figure 7: VR1 resembles store-operated channels.
Figure 8: VR1 resembles store-operated channels.
Figure 9: Vanilloid receptor expression is restricted to sensory neurons.
Figure 10: Vanilloid receptor expression is restricted to sensory neurons.
Figure 11: VR1 is activated by noxious thermal stimuli.
Figure 12: VR1 is activated by noxious thermal stimuli.
Figure 13: Hydrogen ions potentiate the effect of capsaicin on VR1.

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References

  1. Fields, H. L. Pain(McGraw-Hill, New York, (1987)).

    Google Scholar 

  2. Szolcsanyi, J. in Capsaicin in the Study of Pain(ed. Wood, J.) 1–26 (Academic, London, (1993)).

    Google Scholar 

  3. Campbell, E. in Capsaicin and the Study of Pain(ed. Wood, J.) 255–272 (Academic, London, (1993)).

    Google Scholar 

  4. Szallasi, A. & Blumberg, P. M. Vanilloid receptors: new insights enhance potential as a therapeutic target. Pain 68, 195–208 (1996).

    Article  CAS  Google Scholar 

  5. Jancso, G., Kiraly, E. & Jancso-Gaborr, A. Pharmacologically induced selective degeneration of chemosensitive primary sensory neurons. Nature 270, 741–743 (1977).

    Article  ADS  CAS  Google Scholar 

  6. James, I. F., Ninkina, N. N. & Wood, J. N. in Capsaicin in the Study of Pain(ed. Wood, J. N.) 83–104 (Academic, London, (1993)).

    Google Scholar 

  7. Bevan, S. & Szolcsanyi, J. Sensory neuron-specific actions of capsaicin: mechanisms and applications. Trends Pharmacol. Sci. 11, 330–333 (1990).

    Article  CAS  Google Scholar 

  8. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Feigin, A. M., Aaronov, E. V., Bryant, B. P., Teeter, J. H. & Brand, J. G. Capsaicin and its analogs induce ion channels in planar lipid bilayers. Neuroreport 6, 2134–2136 (1995).

    Article  CAS  Google Scholar 

  11. Szolcsanyi, J. & Jancso-Gaborr, A. Sensor effects of capsaicin congeners I. Relationship between chemical structure and pain-producing potency of pungent agents. Drug Res. 25, 1877–1881 (1975).

    CAS  Google Scholar 

  12. Szolcsanyi, J. & Jancso-Gaborr, A. Sensory effects of capsaicin congeners II. Importance of chemical structure and pungency in desensitizing activity of capsaicin-like compounds. Drug Res. 26, 33–37 (1976).

    CAS  Google Scholar 

  13. Bevan, S. et al. Capsazepine: a competitive antagonist of the sensory neuron excitant capsaicin. Br. J. Pharmacol. 107, 544–552 (1992).

    Article  CAS  Google Scholar 

  14. deVries, D. J. & Blumberg, P. M. Thermoregulatory effects of resiniferatoxin in the mouse: comparison with capsaicin. Life Sci. 44, 711–715 (1989).

    Article  CAS  Google Scholar 

  15. Szallasi, A. & Blumberg, P. M. Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper. Neuroscience 30, 515–520 (1989).

    Article  CAS  Google Scholar 

  16. Szallasi, A. The vanilloid (capsaicin) receptor: Receptor types and species specificity. Gen. Pharmacol. 25, 223–243 (1994).

    Article  CAS  Google Scholar 

  17. 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  Google Scholar 

  18. Tsien, R. Y. Fluorescent probes of cell signaling. Annu. Rev. Neurosci. 12, 227–253 (1989).

    Article  CAS  Google Scholar 

  19. Winter, J., Dray, A., Wood, J. N., Yeats, J. C. & Bevan, S. Cellular mechanism of action of resiniferatoxin: a potent sensory neuron excitotoxin. Brain Res. 520, 131–140 (1990).

    Article  CAS  Google Scholar 

  20. Liu, L. & Simon, S. A. Arapid capsaicin-activated current in rat trigeminal ganglion neurons. Proc. Natl Acad. Sci. USA 91, 738–741 (1994).

    Article  ADS  CAS  Google Scholar 

  21. Scoville, W. Note on capsicums. J. Am. Pharm. Assoc. 1, 453–454 (1912).

    CAS  Google Scholar 

  22. Woodbury, J. E. Determination of capsicum pungency by high pressure liquid chromatography and spectrofluorometric determination. J. Assoc. Official Anal. Chem. 63, 556–558 (1980).

    CAS  Google Scholar 

  23. Berkley, R. & Jacobson, E. Peppers: A Cookbook(Simon and Schuster, New York, (1992)).

    Google Scholar 

  24. Mayer, M. L. & Westbrook, G. L. Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurons. J. Physiol. (Lond.) 394, 501–527 (1987).

    Article  CAS  Google Scholar 

  25. Seguela, P., Wadiche, J., Dineley-Miller, K., Dani, J. A. & Patrick J. W. Molecular cloning functionalpropertie and distribution of rat brain a7: a nicotinic cation channel highly permeable to calcium. J. Neurosci. 13 functionalpropertie 596–604 (1993).

  26. Yeats, J. C., Docherty, R. J. & Bevan, S. Calcium-dependent and -independent desensitization of capsaicin-evoked responses in voltage-clamped adult rat dorsal root ganglion (DRG) neurones in culture. J. Physiol. (Lond.) 446, 390 (1992).

    Article  Google Scholar 

  27. Holzer, P. Capsaicin: Cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol. Rev. 43, 143–201 (1991).

    CAS  PubMed  Google Scholar 

  28. Forbes, C. A. & Bevan, S. Single channels activated by capsaicin in patches of membrane from adult rat sensory neurones in culture. Neurosci. Lett. (suppl.) 32, S3 (1988).

    Google Scholar 

  29. Crem, R. J., Fechheimer, M. & MIller, L. K. Prevention of apoptosis by a Bacculovirus gene during infection of insect cells. Science 254, 1388–1390 (1991).

    Article  ADS  Google Scholar 

  30. Choi, D. W. Glutamate receptors and the induction of excitotoxic neuronal death. Prog. Brain Res. 100, 47–51 (1994).

    Article  CAS  Google Scholar 

  31. Hong, K. & Driscoll, M. Atransmembrane domain of the putative channel subunit MEC-4 influences mechanotransduction and neurodegeneration in C. elegans. Nature 367, 470–473 (1994).

    Article  ADS  CAS  Google Scholar 

  32. Montell, C. & Rubin, G. M. Molecular characterization of the Drosophila trp locus: A putative integral membrane protein required for phototransduction. Neuron 2, 1313–1323 (1989).

    Article  CAS  Google Scholar 

  33. Hardie, R. C. & Minke, B. Novel Ca2+ channels underlying transduction in Drosophila photoreceptors: implications for phosphoinositide-mediated Ca2+ mobilization. Trends Neurosci. 16, 371–376 (1993).

    Article  CAS  Google Scholar 

  34. Clapham, D. E. TRP is cracked, but is CRAC TRP? Neuron 16, 1069–1072 (1996).

    Article  CAS  Google Scholar 

  35. Petersen, C. C. H., Berridge, M. J., Borgese, M. F. & Bennett, D. L. Putative capacitative calcium entry channels: expression of Drosophila trp and evidence for the existence of vertebrate homologs. Biochem. J. 311, 41–44 (1995).

    Article  CAS  Google Scholar 

  36. Merritt, J. E. et al. SK&F 96365, a novel inhibitor of receptor-mediated calcium entry. Biochem. J. 271, 515–522 (1990).

    Article  CAS  Google Scholar 

  37. Satinoff, E. Behavioral thermoregulation in response to local cooling of the rat brain. Am. J. Physiol. 206, 1389–1394 (1964).

    Article  CAS  Google Scholar 

  38. Bevan, S. & Geppetti, P. Protons: small stimulants of capsaicin-sensitive sensory nerves. Trends Neurosci. 17, 509–512 (1994).

    Article  CAS  Google Scholar 

  39. Petersen, M. & LaMotte, R. H. Effect of protons on the inward current evoked by capsaicin in isolated dorsal root ganglion cells. Pain 54, 37–42 (1993).

    Article  CAS  Google Scholar 

  40. Kress, M., Fetzer, S., Reeh, P. W. & Vyklicky, L. Low pH facilitates capsaicin responses in isolated sensory neurons of the rat. Neurosci. Lett. 211, 5–8 (1996).

    Article  CAS  Google Scholar 

  41. Snyder, S. H. Opiate receptors and internal opiates. Sci. Am. 236, 44–56 (1977).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  43. Reichling, D. B. & Levine, J. D. Heat transduction in rat sensory neurons by calcium-dependent activation of a cation channel. Proc. Natl Acad. Sci. USA 94, 7006–7011 (1997).

    Article  ADS  CAS  Google Scholar 

  44. Amann, R., Donnerer, J. & Lembeck, F. Activation of primary afferent neurons by thermal stimulation: influence of Ruthenium Red. Naunyn Schmiedeberg's Arch. Pharmacol. 341, 108–113 (1990).

    Article  CAS  Google Scholar 

  45. Kirschstein, T., Busselberg, D. & Treede, R. D. Coexpression of heat-evoked and capsaicin-evoked inward currents in acutely dissociated rat dorsal root ganglion neurons. Neurosci. Lett. 231, 33–36 (1997).

    Article  CAS  Google Scholar 

  46. Brake, A., Wagenbach, M. J. & Julius, D. New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor. Nature 371, 519–523 (1994).

    Article  ADS  CAS  Google Scholar 

  47. Hopp, T. P. & Woods, K. R. Prediction of protein antigenic determinants from amino acid sequences. Proc. Natl Acad. Sci. USA 78, 3824–3828 (1981).

    Article  ADS  CAS  Google Scholar 

  48. Valera, S. et al. Anew class of ligand-gated ion channel defined by P2X receptor for extracellular ATP. Nature 371, 516–519 (1994).

    Article  ADS  CAS  Google Scholar 

  49. Cathala, G. et al. Laboratory methods: A method for isolation of intact, translationally active ribonucleic acid. DNA 2, 329–335 (1983).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank H. Kong, M. Chao and A. Brake for the dorsal root ganglian cDNA and plasmid DNA used in library construction; T. Livelli for HEK293 cells and advice regarding transfection; J.Trafton for guidance with calcium imaging proceudres; N. Guy for tissue sections; J. Poblete for technical assistance; A. Basbaum and M. Dallman for comments on the manuscript; and A. Brake and H.Ingraham for advice and encouragement. M.J.C. is a recipient of an American Cancer Society postdoctoral fellowship and a NARSAD young investigator award. This work was supported by grants from the NIH.

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Caterina, M., Schumacher, M., Tominaga, M. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997). https://doi.org/10.1038/39807

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