title: TRPA1 underlies a sensing mechanism for O2.
abstract: 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.
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kiyonaka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Numata
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kozai
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Naito
authors.forename: Ellen
authors.initials: E
authors.lastname: Knevels
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Toru
authors.initials: T
authors.lastname: Oga
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
authors.forename: Seiji
authors.initials: S
authors.lastname: Suga
authors.forename: Toshiki
authors.initials: T
authors.lastname: Nokami
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Yoshida
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D000860:Hypoxia; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen