H2S FUNCTIONS AS A NOCICEPTIVE MESSENGER THROUGH TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1) ACTIVATION
H2S FUNCTIONS AS A NOCICEPTIVE MESSENGER THROUGH TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1) ACTIVATION
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DOI：
10.1016/j.neuroscience.2012.05.044
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发表时间：
2012-08-30
期刊：
影响因子：
3.3
通讯作者：
Ohta, T.
中科院分区：
文献类型：
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作者：
Ogawa, H.;Takahashi, K.;Ohta, T.
硫化氢（H2S）是一种内源性气体递质，可调节多种生物功能，包括伤害感受。已知H2S引起神经源性炎症和兴奋性痛觉过敏。本研究利用TRPA 1基因缺陷小鼠（TRPA 1（-/-））和异源表达系统，研究了硫化氢激活小鼠瞬时受体电位锚蛋白1（TRPA 1）通道并诱发急性疼痛。在野生型小鼠感觉神经元中，H2S增加了细胞内Ca 2+浓度（[Ca 2 +]（i）），这被钌红（一种非选择性TRP通道阻断剂）和HC-030031（一种TRPA 1阻断剂）抑制。H2S反应性神经元与TRPA 1激动剂敏感性神经元高度对应。[Ca2+]（i）在瞬时受体电位香草素1（TRPV 1（-/-））小鼠的神经元中观察到对H2S的反应，但在TRPA 1（-/-）小鼠的神经元中未观察到对H2S的反应。异源表达的小鼠TRPA 1，但不是小鼠TRPV 1，被H2S激活。还原剂二硫苏糖醇（dithiothreitol）可抑制H_2S诱导的[Ca ~（2+）]（i）反应。对TRPA 1突变体通道的分析表明，位于N-末端内部结构域的两个半胱氨酸残基负责H2S的激活。将H2S足底注射到小鼠后爪中引起急性疼痛，这在TRPA 1（-/-）小鼠中显著较少。[Ca2+]（i）;在酸性条件下，感觉神经元和异源表达通道对H2S的反应以及H2S诱导的疼痛相关行为增强。这些结果表明，H2S通过激活TRPA 1通道作为伤害性信使发挥作用。TRPA 1可能是H2S相关痛觉作用的治疗靶点，特别是在炎症条件下。(C)2012年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Hydrogen sulfide (H2S), an endogenous gasotransmitter, modulates various biological functions, including nociception. It is known that H2S causes neurogenic inflammation and elicits hyperalgesia. Here we show that H2S activates mouse transient receptor potential ankyrin 1 (TRPA1) channels and elicits acute pain, using TRPA1-gene deficient mice (TRPA1(-/-)) and heterologous expression system. In wild-type mouse sensory neurons, H2S increased the intracellular Ca2+ concentration ([Ca2+](i)), which was inhibited by ruthenium red (a nonselective TRP channel blocker) and HC-030031 (a TRPA1 blocker). H2S-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. [Ca2+](i) responses to H2S were observed in neurons from transient receptor potential vanilloid 1 (TRPV1(-/-)) mice but not from TRPA1(-/-) mice. Heterologously expressed mouse TRPA1, but not mouse TRPV1, was activated by H2S. H2S-induced [Ca2+](i) responses were inhibited by dithiothreitol, a reducing agent. Analyses of the TRPA1 mutant channel revealed that two cysteine residues located in the N-terminal internal domain were responsible for the activation by H2S. Intraplantar injection of H2S into the mouse hind paw caused acute pain which was significantly less in TRPA1(-/-) mice. The [Ca2+](i); responses to H2S in sensory neurons and in heterologously expressed channels, and pain-related behavior induced by H2S were enhanced under acidic conditions. These results suggest that H2S functions as a nociceptive messenger through the activation of TRPA1 channels. TRPA1 may be a therapeutic target for H2S-related algesic action, especially under inflammatory conditions. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.