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開催日 2014/9/11
時間 10:00 - 11:00
会場 Room J(313+314)
Chairperson(s) 中川 貴之 / Takayuki Nakagawa (京都大学医学部附属病院 薬剤部 / Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan)
鈴木 えみ子 / Emiko Suzuki (国立遺伝学研究所 構造遺伝学研究センター / Structural biology Center, National Institute of Genetics, Japan)

Involvement of TRPA1 activation through oxidative modification in oxaliplatin-induced acute peripheral neuropathy

  • O1-J-2-1
  • 中村 彩希 / Saki Nakamura:1 趙 萌 / Meng Zhao:1 三宅 崇仁 / Takahito Miyake:1 浜野 智 / Satoshi Hamano:2 高橋 重成 / Nobuaki Takahashi:2 白川 久志 / Hisashi Shirakawa:1 中川 貴之 / Takayuki Nakagawa:1,3 森 泰生 / Yasuo Mori:2 金子 周司 / Shuji Kaneko:1 
  • 1:京都大院・薬・生体機能解析 / Dept. Mol. Pharmacol., Grad. Sch. Pharmaseu. Sci., Kyoto Univ., Kyoto, Japan 2:京都大院・工・合成生物化学 / Dept. Synth. Chem. and Biol. Chem., Grad. Sch. of Engineer., Kyoto Univ., Kyoto, Japan 3:京都大学医学部附属病院薬剤部 / Dept. Clin. Pharmacol. Ther., Kyoto Univ. Hosp., Kyoto, Japan 

Oxaliplatin (OHP), a platinum-based chemotherapeutic agent, causes peculiar acute peripheral neuropathy, which is triggered or exacerbated by cold. We recently reported that OHP-induced acute cold hypersensitivity is caused by the enhanced responsiveness of TRPA1 channel in mice. Here, we investigated the molecular mechanism of TRPA1 activation and sensitization by OHP in HEK293T cells expressing human TRPA1. In Ca2+ imaging and patch-clamp tests, OHP (0.3-1 mM) evoked Ca2+ response and increased whole-cell currents. The OHP-induced Ca2+ respons was abolished by a TRPA1 antagonist or a reactive oxygen species (ROS) scavenger. TRPA1 is activated by oxidation of cysteine residues or dehydroxylation of proline residue located in N-terminal of TRPA1. OHP-induced Ca2+ response was attenuated in several TRPA1 mutants of the cysteine residues to serine, but not in a mutant of the proline residue to alanine. In addition, H2O2-specific indicator showed that OHP increased H2O2 production. These data suggest that oxidative cysteine modification by OHP-produced ROS could activate TRPA1. However, cisplatin (1 mM) also activated TRPA1, indicationg ROS-mediated TRPA1 activation is not peculiar to OHP. On the other hand, treatment with OHP (100 μM), but not cisplatin (100 μM), for 2 hr increased H2O2-evoked Ca2+ response and single channel TRPA1 currents. When mice were treated with OHP (5 mg/kg) for 2 hr, H2O2-evoked nocifensive behaviors were significantly enhanced. Taken together, these results suggest that treatment with OHP could increase TRPA1 sensitivity to ROS, and subsequently the sensitized TRPA1 is activated by ROS produced by platinum compounds, which may contribute to the OHP-induced acute peripheral neuropathy.

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