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TRPA1 underlies a sensing mechanism for O2

Nature Chemical Biology volume 7, pages 701–711 (2011)Cite this article

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Abstract

Oxygen (O2) is a prerequisite for cellular respiration in aerobic organisms but also elicits toxicity. To understand how animals cope with the ambivalent physiological nature of O2, it is critical to elucidate the molecular mechanisms responsible for O2 sensing. Here our systematic evaluation of transient receptor potential (TRP) cation channels using reactive disulfides with different redox potentials reveals the capability of TRPA1 to sense O2. O2 sensing is based upon disparate processes: whereas prolyl hydroxylases (PHDs) exert O2-dependent inhibition on TRPA1 activity in normoxia, direct O2 action overrides the inhibition via the prominent sensitivity of TRPA1 to cysteine-mediated oxidation in hyperoxia. Unexpectedly, TRPA1 is activated through relief from the same PHD-mediated inhibition in hypoxia. In mice, disruption of the Trpa1 gene abolishes hyperoxia- and hypoxia-induced cationic currents in vagal and sensory neurons and thereby impedes enhancement of in vivo vagal discharges induced by hyperoxia and hypoxia. The results suggest a new O2-sensing mechanism mediated by TRPA1.

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Figure 1: The prominent oxidation reactivity confers O2 sensitivity on TRPA1.
Figure 2: O2 directly activates TRPA1 through cysteine modification.
Figure 3: Hypoxia activates TRPA1.
Figure 4: TRPA1 protein is susceptible to proline hydroxylation by PHDs.
Figure 5: TRPA1 is activated by relief from O2-dependent inhibition by proline hydroxylation.
Figure 6: TRPA1 mediates hyperoxia- and hypoxia-induced cationic currents in vagal and sensory neurons.
Figure 7: Defects of discharges in vagal afferents of Trpa1 knockout mice under systemic hypoxia and hyperoxia.
Figure 8: Molecular mechanism underlying O2-sensing in TRPA1 channel.

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Acknowledgements

We thank D. Julius, T. Yoshida and M. Wakamori for experimental advice, T. Miki and J. Ikenouchi for helpful discussions, and T. Morii and I. Hamachi for their support in DTNB-2Bio synthesis. We are also grateful to T. Niidome, H. Shirakawa and T. Nakagawa for their support in mouse experiments.

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Authors and Affiliations

  1. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan

    Nobuaki Takahashi, Shigeki Kiyonaka, Tomohiro Numata, Daisuke Kozai, Yusuke Mizuno, Shinichiro Yamamoto, Seiji Suga, Toshiki Nokami, Jun-ichi Yoshida & Yasuo Mori

  2. Department of Technology and Ecology, Hall of Global Environmental Studies, Kyoto University, Kyoto, Japan

    Nobuaki Takahashi, Shigeki Kiyonaka, Tomohiro Numata, Daisuke Kozai, Yusuke Mizuno, Shinichiro Yamamoto & Yasuo Mori

  3. Advanced Biomedical Engineering Research Unit, Kyoto University, Kyoto, Japan

    Nobuaki Takahashi

  4. Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

    Tomoyuki Kuwaki

  5. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan

    Shigeki Kiyonaka & Yasuo Mori

  6. Division of Pathology, National Ureshino Hospital, Ureshino, Japan

    Shinji Naito

  7. Vesalius Research Center, Catholic University of Leuven, Leuven, Belgium

    Ellen Knevels & Peter Carmeliet

  8. Vesalius Research Center, Flanders Institute for Biotechnology, Leuven, Belgium

    Ellen Knevels & Peter Carmeliet

  9. Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Toru Oga

  10. Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Shuji Kaneko

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Contributions

N.T., S. Kiyonaka, Y. Mizuno and Y. Mori initiated and designed the project. N.T., S. Kiyonaka, T. Numata, D.K., Y. Mizuno, S.Y., S.N., T.O., S. Kaneko and T. Nokami performed experiments and analyzed data. T.K. supervised in vivo studies. S.S. and J.Y. supervised the electrochemical experiments. E.K. and P.C. established Phd1 knockout and Phd3 knockout mouse lines subjected to the experiment. N.T., T.K., S. Kiyonaka, T. Numata, D.K. and Y. Mori wrote the manuscript. Y. Mori directed the research. All authors discussed and commented on the manuscript.

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Correspondence to Yasuo Mori.

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Takahashi, N., Kuwaki, T., Kiyonaka, S. et al. TRPA1 underlies a sensing mechanism for O2. Nat Chem Biol 7, 701–711 (2011). https://doi.org/10.1038/nchembio.640

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