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.
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DOI：
10.1038/ncomms12840
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发表时间：
2016-09-15
影响因子：
16.6
通讯作者：
Kaneko, Shuji
中科院分区：
文献类型：
--
作者：
Miyake, Takahito;Nakamura, Saki;Zhao, Meng;So, Kanako;Inoue, Keisuke;Numata, Tomohiro;Takahashi, Nobuaki;Shirakawa, Hisashi;Mori, Yasuo;Nakagawa, Takayuki;Kaneko, Shuji
哺乳动物瞬时受体电位锚蛋白1（TRPA 1）是一种多模式的伤害感受器，在疼痛产生中起重要作用，但其作为冷伤害感受器的作用仍有争议。在这里，我们提出TRPA 1可以通过活性氧（ROS）信号转导来感受有害的寒冷。我们发现，抑制羟基化的脯氨酸残基内的N-末端锚蛋白重复的人TRPA 1突变或使用脯氨酰羟化酶（PHD）抑制剂增强了过氧化氢的存在下TRPA 1的冷敏感性。在小鼠中抑制PHD触发小鼠TRPA 1致敏，足以感知冷诱发的ROS，这导致冷超敏反应。此外，这种现象是化疗剂奥沙利铂或其代谢物草酸盐诱导的急性冷超敏反应的基础。因此，我们的研究结果提供了证据表明，阻断脯氨酰羟基化揭示了TRPA 1对ROS的敏感性，这使得TRPA 1能够将ROS信号传导转化为冷敏感性。 瞬时受体电位锚蛋白1（TRPA 1）是一种参与伤害性疼痛感知的阳离子通道。在这里，作者表明TRPA 1 N端脯氨酸的羟基化使其对有害寒冷引起的活性氧敏感。
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. The transient receptor potential ankyrin 1 (TRPA1) is a cation channel that is involved in nociceptive pain sensing. Here, the authors show that hydroxylation of a proline in the N terminus of TRPA1 renders it sensitive to reactive oxygen species resulting from noxious cold.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
16.6
作者：
Chen, Jun;Kang, Dawon;Xu, Jing;Lake, Marc;Hogan, James O.;Sun, Chaohong;Walter, Karl;Yao, Betty;Kim, Donghee
通讯作者：
Kim, Donghee
DOI：
10.1523/jneurosci.5369-07.2008
发表时间：
2008-03-05
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Andersson DA;Gentry C;Moss S;Bevan S
通讯作者：
Bevan S
影响因子：
3.4
作者：
Bobkov, Y. V.;Corey, E. A.;Ache, B. W.
通讯作者：
Ache, B. W.
影响因子：
5.3
作者：
Avenali, Luca;Narayanan, Pratibha;Schmidt, Manuela
通讯作者：
Schmidt, Manuela