TRPA1 underlies a sensing mechanism for O2

The redox-sensitive TRP channel TRPA1 is activated in hyperoxic and hypoxic conditions directly through modification of cysteine residues by O 2 and indirectly through prolyl hydroxylation by PHDs, enzymes related to the hypoxia-inducible factor HIF-1, thus helping to explain how O 2 is sensed by sensory and vagal neurons. 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.