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

被引：69

作者：

Miyake, Takahito ^{[1
]}

Nakamura, Saki ^{[1
]}

Zhao, Meng ^{[1
]}

So, Kanako ^{[1
]}

Inoue, Keisuke ^{[2
]}

Numata, Tomohiro ^{[2
,3
]}

Takahashi, Nobuaki ^{[2
]}

Shirakawa, Hisashi ^{[1
]}

Mori, Yasuo ^{[2
]}

Nakagawa, Takayuki ^{[1
,4
]}

Kaneko, Shuji ^{[1
]}

机构：

[1] Kyoto Univ, Grad Sch Pharmaceut Sci, Dept Mol Pharmacol, Sakyo Ku, 46-29 Yoshida Shimoadachi Cho, Kyoto, Kyoto 6068501, Japan

[2] Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Nishikyo Ku, Katsura Campus, Kyoto, Kyoto 6158510, Japan

[3] Fukuoka Univ, Grad Sch Med Sci, Dept Physiol, Jonan Ku, Nanakuma 7-45-1, Fukuoka, Fukuoka 8140180, Japan

[4] Kyoto Univ Hosp, Dept Clin Pharmacol & Therapeut, Sakyo Ku, 54 Shogoin Kawahara Cho, Kyoto, Kyoto 6068507, Japan

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

ION-CHANNEL TRPA1; MOLECULAR DETERMINANT; NOCICEPTIVE NEURONS; PAIN; OXALIPLATIN; HYPERSENSITIVITY; MICE; CONTRIBUTES; RECEPTOR; CALCIUM;

D O I：

10.1038/ncomms12840

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

共 56 条

[1] Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress [J].