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