title: Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS.
abstract: Mammalian transient receptor potential ankyrin 1 (TRPA1) is a polymodal nociceptor that plays an important role in pain generation, but its role as a cold nociceptor is still controversial. Here, we propose that TRPA1 can sense noxious cold via transduction of reactive oxygen species (ROS) signalling. We show that inhibiting hydroxylation of a proline residue within the N-terminal ankyrin repeat of human TRPA1 by mutation or using a prolyl hydroxylase (PHD) inhibitor potentiates the cold sensitivity of TRPA1 in the presence of hydrogen peroxide. Inhibiting PHD in mice triggers mouse TRPA1 sensitization sufficiently to sense cold-evoked ROS, which causes cold hypersensitivity. Furthermore, this phenomenon underlies the acute cold hypersensitivity induced by the chemotherapeutic agent oxaliplatin or its metabolite oxalate. Thus, our findings provide evidence that blocking prolyl hydroxylation reveals TRPA1 sensitization to ROS, which enables TRPA1 to convert ROS signalling into cold sensitivity.
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku 606-8501, Japan.
authors.forename: Takahito
authors.identifier: 0000-0002-4356-5883
authors.initials: T
authors.lastname: Miyake
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku 606-8501, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku 606-8501, Japan.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku 606-8501, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: So
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Enginnering, Kyoto University, Katsura Campus, Nishikyo-ku 615-8510, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Enginnering, Kyoto University, Katsura Campus, Nishikyo-ku 615-8510, Japan.|Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Nanakuma 7-45-1, Jonan-ku 814-0180, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Numata
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Enginnering, Kyoto University, Katsura Campus, Nishikyo-ku 615-8510, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku 606-8501, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shirakawa
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Enginnering, Kyoto University, Katsura Campus, Nishikyo-ku 615-8510, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku 606-8501, Japan.|Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku 606-8507, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku 606-8501, Japan.
authors.forename: Shuji
authors.identifier: 0000-0001-5152-5809
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D056587:Cryopyrin-Associated Periodic Syndromes / Q000139:chemically induced* / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009944:Organoplatinum Compounds / Q000009:adverse effects; D000077150:Oxaliplatin; D061251:Primary Cell Culture; D064800:Prolyl-Hydroxylase Inhibitors / Q000009:adverse effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000074025:TRPA1 Cation Channel / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D064800:Prolyl-Hydroxylase Inhibitors; D017382:Reactive Oxygen Species; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; C475685:Trpa1 protein, mouse; D000077150:Oxaliplatin