1. Academic Validation
  2. Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS

Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS

  • Nat Commun. 2016 Sep 15;7:12840. doi: 10.1038/ncomms12840.
Takahito Miyake 1 Saki Nakamura 1 Meng Zhao 1 Kanako So 1 Keisuke Inoue 2 Tomohiro Numata 2 3 Nobuaki Takahashi 2 Hisashi Shirakawa 1 Yasuo Mori 2 Takayuki Nakagawa 1 4 Shuji Kaneko 1
Affiliations

Affiliations

  • 1 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku 606-8501, Japan.
  • 2 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Enginnering, Kyoto University, Katsura Campus, Nishikyo-ku 615-8510, Japan.
  • 3 Department of Physiology, Graduate School of Medical Sciences, Fukuoka University, Nanakuma 7-45-1, Jonan-ku 814-0180, Japan.
  • 4 Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku 606-8507, Japan.
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.

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