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Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels

Abstract

Carvacrol, eugenol and thymol are major components of plants such as oregano, savory, clove and thyme. When applied to the tongue, these flavors elicit a warm sensation. They are also known to be skin sensitizers and allergens. The transient receptor potential channel (TRPV3) is a warm-sensitive Ca2+-permeable cation channel highly expressed in the skin, tongue and nose. Here we show that TRPV3 is strongly activated and sensitized by carvacrol, thymol and eugenol. Tongue and skin epithelial cells respond to carvacrol and eugenol with an increase in intracellular Ca2+ levels. We also show that this TRPV3 activity is strongly potentiated by phospholipase C–linked, G protein–coupled receptor stimulation. In addition, carvacrol activates and rapidly desensitizes TRPA1, which may explain the pungency of oregano. Our results support a role for temperature-sensitive TRP channels in chemesthesis in oral and nasal epithelium and suggest that TRPV3 may be a molecular target of plant-derived skin sensitizers.

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Figure 1: TRPV3 mRNA is highly expressed in the tongue and nasal epithelium.
Figure 2: TRPV3 protein is highly expressed in the tongue and nasal epithelium.
Figure 3: Carvacrol increases [Ca2+]i in TRPV3-expressing HEK293 cells and tongue epithelial cells.
Figure 4: TRPV3 is activated by carvacrol, thymol, vanillin and ethyl-vanillin and sensitized by warmth.
Figure 5: Carvacrol also activates TRPA1.
Figure 6: Eugenol activates TRPV3 and induces IL-1α release in mouse keratinocytes.
Figure 7: Eugenol activates and sensitizes TRPV3 in HEK293 cells and activates TRPV3-like current in the mouse keratinocytes.
Figure 8: Sensitization of TRPV3 by PLC-coupled receptor stimulation.

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References

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

    Article  CAS  Google Scholar 

  2. Peier, A.M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002).

    Article  CAS  Google Scholar 

  3. McKemy, D.D., Neuhausser, W.M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002).

    Article  CAS  Google Scholar 

  4. Bryant, B. & Silver, W.L. in The Neurobiology of Taste and Smell (eds. Finger, T.E., Silver, W.L. & Restrepo, D.) (Wiley-Liss, New York, 2000).

    Google Scholar 

  5. US Food and Drug Administration. Spices - definitions <http://www.fda.gov/ora/compliance_ref/cpg/cpgfod/cpg525-750.html>.

  6. Scholl, I. & Jensen-Jarolim, E. Allergenic potency of spices: hot, medium hot, or very hot. Int. Arch. Allergy Immunol. 135, 247–261 (2004).

    Article  Google Scholar 

  7. Corsini, E., Primavera, A., Marinovich, M. & Galli, C.L. Selective induction of cell-associated interleukin-1alpha in murine keratinocytes by chemical allergens. Toxicology 129, 193–200 (1998).

    Article  CAS  Google Scholar 

  8. Xu, H. et al. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418, 181–186 (2002).

    Article  CAS  Google Scholar 

  9. Finger, T.E. & Simon, S.A. in The neurobiology of taste and smell (ed. Finger, T. E., Silver, W.L. & Restrepo, D.) (Wiley-Liss, New York, 2000).

    Google Scholar 

  10. Peier, A.M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002).

    Article  CAS  Google Scholar 

  11. Hu, H.Z. et al. 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J. Biol. Chem. 279, 35741–35748 (2004).

    Article  CAS  Google Scholar 

  12. Chung, M.K., Lee, H., Mizuno, A., Suzuki, M. & Caterina, M.J. 2-aminoethoxydiphenyl borate activates and sensitizes the heat-gated ion channel TRPV3. J. Neurosci. 24, 5177–5182 (2004).

    Article  CAS  Google Scholar 

  13. Moqrich, A. et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307, 1468–1472 (2005).

    Article  CAS  Google Scholar 

  14. Smith, G.D. et al. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418, 186–190 (2002).

    Article  CAS  Google Scholar 

  15. Belitz, H.-D., Grosch, W. & Schieberle, P. in Food Chemistry (eds. Belitz, H.-D., Grosch, W. & Schieberle, P.) (Springer, Berlin, 2004).

    Book  Google Scholar 

  16. Chung, M.K., Guler, A.D. & Caterina, M.J. Biphasic currents evoked by chemical or thermal activation of the heat-gated ion channel, TRPV3. J. Biol. Chem. 280, 15928–15941 (2005).

    Article  CAS  Google Scholar 

  17. Xu, H., Blair, N.T. & Clapham, D.E. Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J. Neurosci. 25, 8924–8937 (2005).

    Article  CAS  Google Scholar 

  18. Jordt, S.E. et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260–265 (2004).

    Article  CAS  Google Scholar 

  19. Macpherson, L.J. et al. The pungency of garlic: Activation of TRPA1 and TRPV1 in response to allicin. Curr. Biol. 15, 929–934 (2005).

    Article  CAS  Google Scholar 

  20. Bautista, D.M. et al. Pungent products from garlic activate the sensory ion channel TRPA1. Proc. Natl. Acad. Sci. USA 102, 12248–12252 (2005).

    Article  CAS  Google Scholar 

  21. Corsini, E. & Galli, C.L. Cytokines and irritant contact dermatitis. Toxicol. Lett. 102–103, 277–282 (1998).

    Article  Google Scholar 

  22. Barker, J.N., Mitra, R.S., Griffiths, C.E., Dixit, V.M. & Nickoloff, B.J. Keratinocytes as initiators of inflammation. Lancet 337, 211–214 (1991).

    Article  CAS  Google Scholar 

  23. Effendy, I., Loffler, H. & Maibach, H.I. Epidermal cytokines in murine cutaneous irritant responses. J. Appl. Toxicol. 20, 335–341 (2000).

    Article  CAS  Google Scholar 

  24. Chung, M.K., Lee, H., Mizuno, A., Suzuki, M. & Caterina, M.J. TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J. Biol. Chem. 279, 21569–21575 (2004).

    Article  CAS  Google Scholar 

  25. Lee, H. & Caterina, M.J. TRPV channels as thermosensory receptors in epithelial cells. Pflugers Arch. 451, 160–167 (2005).

    Article  CAS  Google Scholar 

  26. Lewis, R.S. Calcium oscillations in T-cells: mechanisms and consequences for gene expression. Biochem. Soc. Trans. 31, 925–929 (2003).

    Article  CAS  Google Scholar 

  27. Lee, M.H. et al. Eugenol inhibits calcium currents in dental afferent neurons. J. Dent. Res. 84, 848–851 (2005).

    Article  CAS  Google Scholar 

  28. Berova, N., Stransky, L. & Krasteva, M. Studies on contact dermatitis in stomatological staff. Dermatol. Monatsschr. 176, 15–18 (1990).

    CAS  PubMed  Google Scholar 

  29. Yang, B.H. et al. Activation of vanilloid receptor 1 (VR1) by eugenol. J. Dent. Res. 82, 781–785 (2003).

    Article  CAS  Google Scholar 

  30. Jordt, S.E. & Julius, D. Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108, 421–430 (2002).

    Article  CAS  Google Scholar 

  31. Kinnamon, S.C. & Margolskee, R.F. Mechanisms of taste transduction. Curr. Opin. Neurobiol. 6, 506–513 (1996).

    Article  CAS  Google Scholar 

  32. Zhang, Y. et al. Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell 112, 293–301 (2003).

    Article  CAS  Google Scholar 

  33. Katada, S., Hirokawa, T., Oka, Y., Suwa, M. & Touhara, K. Structural basis for a broad but selective ligand spectrum of a mouse olfactory receptor: mapping the odorant-binding site. J. Neurosci. 25, 1806–1815 (2005).

    Article  CAS  Google Scholar 

  34. Finger, T.E. et al. Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration. Proc. Natl. Acad. Sci. USA 100, 8981–8986 (2003).

    Article  CAS  Google Scholar 

  35. Huang, Y.J., Maruyama, Y., Lu, K.S., Pereira, E. & Roper, S.D. Mouse taste buds release serotonin in response to taste stimuli. Chem. Senses 30 (Suppl.), i39–i40 (2005).

    Article  CAS  Google Scholar 

  36. Wang, H. & Woolf, C.J. Pain TRPs. Neuron 46, 9–12 (2005).

    Article  CAS  Google Scholar 

  37. Horowitz, L.F. et al. Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of m current. J. Gen. Physiol. 126, 243–262(2005).

    Article  CAS  Google Scholar 

  38. Koizumi, S., Fujishita, K., Inoue, K., Shigemoto-Mogami, Y. & Tsuda, M. Ca2+ waves in keratinocytes are transmitted to sensory neurons: the involvement of extracellular ATP and P2Y2 receptor activation. Biochem. J. 380, 329–338 (2004).

    Article  CAS  Google Scholar 

  39. Yuspa, S.H., Kulesz-Martin, M., Ben, T. & Hennings, H. Transformation of epidermal cells in culture. J. Invest. Dermatol. 81, 162s–168s (1983).

    Article  CAS  Google Scholar 

  40. Gilbertson, T.A., Roper, S.D. & Kinnamon, S.C. Proton currents through amiloride-sensitive Na+ channels in isolated hamster taste cells: enhancement by vasopressin and cAMP. Neuron 10, 931–942 (1993).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Sandler Program for Ashma Research and the Howard Hughes Medical Institute. We thank S.H. Yuspa (National Cancer Institute) for providing us with mouse 308 keratinocytes. We thank D. Julius for rat TRPV1, TRPV2, TRPM8 and TRPA1 constructs. M. Caterina and D. Ren provided the mouse TRPV3 and TRPV4 constructs, respectively. We are grateful to U. Berger and H. Wang for assistance. We thank S. Cibulsky, N. Blair, B. Carter, W. Pu, S. Ikeda, C. Medler, S. Roper and members of the Clapham laboratory for discussion and helpful comments.

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Correspondence to David E Clapham.

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The authors have a patent application on TRPV3.

Supplementary information

Supplementary Fig. 1

Specificity of mTRPV3 polyclonal antibody. (PDF 523 kb)

Supplementary Fig. 2

TRPV3 expression in the epithelia surrounding taste buds of circumvallate papillae. (PDF 2120 kb)

Supplementary Fig. 3

Structures of a family of plant-derived phenol-containing compounds. (PDF 16 kb)

Supplementary Fig. 4

Carvacrol increases [Ca2+]i in rat tongue epithelial cells. (PDF 43 kb)

Supplementary Fig. 5

Carvacrol does not activate TRPV1, TRPV2, TRPV4, or TRPM8. (PDF 1027 kb)

Supplementary Fig. 6

Mouse 308 keratinocytes express TRPV3 and display TRPV3-like (ITRPV3_L) currents. (PDF 810 kb)

Supplementary Fig. 7

Eugenol activates TRPV3 but not TRPV2 or TRPV4. (PDF 1596 kb)

Supplementary Fig. 8

Sensitization of ITRPV3 by stimulation of G protein-linked, PLC-coupled receptors. (PDF 784 kb)

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Xu, H., Delling, M., Jun, J. et al. Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat Neurosci 9, 628–635 (2006). https://doi.org/10.1038/nn1692

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