Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
Nat Chem Biol. 2011 Aug 28;7(10):701-11. doi: 10.1038/nchembio.640.
Oxygen (O(2)) is a prerequisite for cellular respiration in aerobic organisms but also elicits toxicity. To understand how animals cope with the ambivalent physiological nature of O(2), it is critical to elucidate the molecular mechanisms responsible for O(2) 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 O(2). O(2) sensing is based upon disparate processes: whereas prolyl hydroxylases (PHDs) exert O(2)-dependent inhibition on TRPA1 activity in normoxia, direct O(2) 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 O(2)-sensing mechanism mediated by TRPA1.
氧气（O(2)）是需氧生物细胞呼吸的前提条件，但也会引发毒性。为了了解动物如何应对 O(2)这种矛盾的生理特性，阐明负责 O(2)感测的分子机制至关重要。在这里，我们使用具有不同氧化还原电位的反应性二硫键对瞬时受体电位 (TRP)阳离子通道进行了系统评估，结果表明 TRPA1 能够感知 O(2)。O(2)感测基于不同的过程：脯氨酰羟化酶 (PHD) 在常氧条件下对 TRPA1 活性发挥 O(2)依赖性抑制作用，而直接的 O(2)作用通过 TRPA1 对高氧中半胱氨酸介导的氧化的显著敏感性来克服抑制作用。出乎意料的是，TRPA1 通过从 PHD 介导的低氧抑制中解脱而被激活。在小鼠中，Trpa1 基因的破坏消除了迷走神经和感觉神经元中高氧和低氧诱导的阳离子电流，从而阻碍了高氧和低氧诱导的体内迷走神经放电的增强。结果表明，TRPA1 介导了一种新的 O(2)感测机制。
