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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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.

Author information

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yasuo Mori.

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DOI

https://doi.org/10.1038/nchembio.640

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