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A single N-terminal cysteine in TRPV1 determines activation by pungent compounds from onion and garlic

Nature Neuroscience volume 11, pages 255–261 (2008)Cite this article

Abstract

Some members of the transient receptor potential (TRP) family of cation channels mediate sensory responses to irritant substances. Although it is well known that TRPA1 channels are activated by pungent compounds found in garlic, onion, mustard and cinnamon extracts, activation of TRPV1 by these extracts remains controversial. Here we establish that TRPV1 is activated by pungent extracts from onion and garlic, as well as by allicin, the active compound in these preparations, and participates together with TRPA1 in the pain-related behavior induced by this compound. We found that in TRPV1 these agents act by covalent modification of cysteine residues. In contrast to TRPA1 channels, modification of a single cysteine located in the N-terminal region of TRPV1 was necessary and sufficient for all the effects we observed. Our findings point to a conserved mechanism of activation in TRP channels, which provides new insights into the molecular basis of noxious stimuli detection.

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Figure 1: DRG neurons respond to onion and garlic extracts and to allicin.
Figure 2: Allicin induces TRPA1- and TRPV1-mediated action potentials and a behavioral pain-like response.
Figure 3: Heterologously expressed TRPV1 channels respond to pungent compounds.
Figure 4: Cysteine-modifying reagents act as activators of TRPV1 channels.
Figure 5: MTSEA increases open probability in TRPV1 in the absence of capsaicin.
Figure 6: A single cysteine is necessary for activation of the TRPV1 channel by cysteine-modifying reagents.
Figure 7: The presence of C157 is sufficient to promote MTSEA effects on TRPV1.
Figure 8: Cysteine C157 is also responsible for the activation of the TRPV1 channel by allicin.

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References

  1. Clapham, D.E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Caterina, M.J. & Julius, D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517 (2001).

    Article  CAS  Google Scholar 

  4. 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 

  5. Block, E. The chemistry of garlic and onions. Sci. Am. 252, 114–119 (1985).

    Article  CAS  Google Scholar 

  6. Block, E. Recent results in the organosulfur and organoselenium chemistry of genus Allium and Brassica plants. Relevance for cancer prevention. Adv. Exp. Med. Biol. 401, 155–169 (1996).

    Article  CAS  Google Scholar 

  7. Calvey, E.M., Roach, J.A. & Block, E. Supercritical fluid chromatography of garlic (Allium sativum) extracts with mass spectrometric identification of allicin. J. Chromatogr. Sci. 32, 93–96 (1994).

    Article  CAS  Google Scholar 

  8. Calvey, E.M., White, K.D., Matusik, J.E., Sha, D. & Block, E. Allium chemistry: identification of organosulfur compounds in ramp (Allium tricoccum) homogenates. Phytochemistry 49, 359–364 (1998).

    Article  CAS  Google Scholar 

  9. Hinman, A., Chuang, H.H., Bautista, D.M. & Julius, D. TRP channel activation by reversible covalent modification. Proc. Natl. Acad. Sci. USA 103, 19564–19568 (2006).

    Article  CAS  Google Scholar 

  10. Macpherson, L.J. et al. Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445, 541–545 (2007).

    Article  CAS  Google Scholar 

  11. Lishko, P.V., Procko, E., Jin, X., Phelps, C.B. & Gaudet, R. The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron 54, 905–918 (2007).

    Article  CAS  Google Scholar 

  12. Jones, M.G. et al. Biosynthesis of the flavor precursors of onion and garlic. J. Exp. Bot. 55, 1903–1918 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Story, G.M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003).

    Article  CAS  Google Scholar 

  15. Jara, A., Islas, L.D., Garcia-Villegas, R. & Rosenbaum, T. On the mechanism of TBA block of the TRPV1 channel. Biophys J. 92, 3901–3914 (2007).

    Article  Google Scholar 

  16. Nilius, B. et al. Gating of TRP channels: a voltage connection? J. Physiol. (Lond.) 567, 35–44 (2005).

    Article  CAS  Google Scholar 

  17. 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 

  18. Vyklicky, L., Lyfenko, A., Susankova, K., Teisinger, J. & Vlachova, V. Reducing agent dithiothreitol facilitates activity of the capsaicin receptor VR-1. Neuroscience 111, 435–441 (2002).

    Article  CAS  Google Scholar 

  19. Susankova, K., Tousova, K., Vyklicky, L., Teisinger, J. & Vlachova, V. Reducing and oxidizing agents sensitize heat-activated vanilloid receptor (TRPV1) current. Mol. Pharmacol. 70, 383–394 (2006).

    CAS  PubMed  Google Scholar 

  20. Cortright, D.N., Krause, J.E. & Broom, D.C. TRP channels and pain. Biochim. Biophys. Acta 1772, 978–988 (2007).

    Article  CAS  Google Scholar 

  21. Venkatachalam, K. & Montell, C. TRP channels. Annu. Rev. Biochem. 76, 387–417 (2007).

    Article  CAS  Google Scholar 

  22. 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 

  23. Bautista, D.M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006).

    Article  CAS  Google Scholar 

  24. Hess, D.T., Matsumoto, A., Kim, S.O., Marshall, H.E. & Stamler, J.S. Protein S-nitrosylation: purview and parameters. Nat. Rev. Mol. Cell Biol. 6, 150–166 (2005).

    Article  CAS  Google Scholar 

  25. Matalon, S. et al. Regulation of ion channel structure and function by reactive oxygen-nitrogen species. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L1184–L1189 (2003).

    Article  CAS  Google Scholar 

  26. Yoshida, T. et al. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat. Chem. Biol. 2, 596–607 (2006).

    Article  CAS  Google Scholar 

  27. Jin, X., Touhey, J. & Gaudet, R. Structure of the N-terminal ankyrin repeat domain of the TRPV2 ion channel. J. Biol. Chem. 281, 25006–25010 (2006).

    Article  CAS  Google Scholar 

  28. Corey, D.P. et al. TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432, 723–730 (2004).

    Article  CAS  Google Scholar 

  29. Howard, J. & Bechstedt, S. Hypothesis: a helix of ankyrin repeats of the NOMPC-TRP ion channel is the gating spring of mechanoreceptors. Curr. Biol. 14, R224–R226 (2004).

    Article  CAS  Google Scholar 

  30. Michaely, P., Tomchick, D.R., Machius, M. & Anderson, R.G. Crystal structure of a 12 ANK repeat stack from human ankyrinR. EMBO J. 21, 6387–6396 (2002).

    Article  CAS  Google Scholar 

  31. Macpherson, L.J. et al. An ion channel essential for sensing chemical damage. J. Neurosci. 27, 11412–11415 (2007).

    Article  CAS  Google Scholar 

  32. Stein, A.T., Ufret-Vincenty, C.A., Hua, L., Santana, L.F. & Gordon, S.E. Phosphoinositide 3–kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane. J. Gen. Physiol. 128, 509–522 (2006).

    Article  CAS  Google Scholar 

  33. Sigworth, F.J. The variance of sodium current fluctuations at the node of Ranvier. J. Physiol. (Lond.) 307, 97–129 (1980).

    Article  CAS  Google Scholar 

  34. Rosenbaum, T. & Gordon, S.E. Dissecting intersubunit contacts in cyclic nucleotide-gated ion channels. Neuron 33, 703–713 (2002).

    Article  CAS  Google Scholar 

  35. Kwan, K.Y. et al. TRPA1 contributes to cold, mechanical, and chemical nociception, but is not essential for hair-cell transduction. Neuron 50, 277–289 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Julius for providing the TRPV1 cDNA and S. Simon and M. Rosenbaum for thoughtful discussion of this manuscript. We also thank L. Ongay, A. Aguilera Jiménez, J. Barbosa, F. Sierra, C. Rivera and H. Malagón for expert technical support and R. Argüello García for his most kind gift of allicin. This work was supported by grants from Dirección General de Asuntos del Personal Académico-Universidad Nacional Autónoma de México (DGAPA-UNAM) IN201705 and IN200308 to T.R. and IN202006–39 to L.D.I. and Consejo Nacional de Ciencia y Tecnología (CONACyT) No. 58038 to T.R., No. 48990/24777 to L.D.I., and No. 43128 to R.G.-V.; and by a grant from the National Eye Institute to S.E.G.

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Author notes

  1. Héctor Salazar, Itzel Llorente and Andrés Jara-Oseguera: These authors contributed equally to this work.

Authors and Affiliations

  1. Departamento de Biofísica, Instituto de Fisiología Celular, Circuito Exterior S/N, Ciudad Universitaria, Universidad Nacional Autónoma de México, México, D.F., 04510, Mexico

    Héctor Salazar, Itzel Llorente, Andrés Jara-Oseguera & Tamara Rosenbaum

  2. Departamento de Fisiología, Facultad de Medicina, Circuito escolar S/N, Ciudad Universitaria, Universidad Nacional Autónoma de México, México, D.F., 04510, Mexico

    Andrés Jara-Oseguera & León D Islas

  3. Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. Instituto Politécnico Nacional 2508, México, D.F., 07360, Mexico

    Refugio García-Villegas

  4. Department of Physiology and Biophysics, University of Washington, 1705 NE Pacific Street, Seattle, 98195, Washington, USA

    Mika Munari & Sharona E Gordon

Authors
  1. Héctor Salazar
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Contributions

H.S., I.L. and A.J.O. contributed equally to this work. I.L. and T.R. carried out all site-directed mutagenesis experiments. H.S., I.L., A.J.O. and L.D.I. performed electrophysiological recordings. R.G.V. and T.R. carried out DRG neuron and behavioral experiments. L.D.I. and T.R. analyzed the data and wrote the manuscript. S.E.G. and M.M. discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Tamara Rosenbaum.

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Salazar, H., Llorente, I., Jara-Oseguera, A. et al. A single N-terminal cysteine in TRPV1 determines activation by pungent compounds from onion and garlic. Nat Neurosci 11, 255–261 (2008). https://doi.org/10.1038/nn2056

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