TRPA1 is a major oxidant sensor in murine airway sensory neurons
TRPA1 is a major oxidant sensor in murine airway sensory neurons
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DOI：
10.1172/jci34192
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发表时间：
2008-05-01
影响因子：
15.9
通讯作者：
Jordt, Sven-Eric
中科院分区：
文献类型：
--
作者：
Bessac, Bret F.;Sivula, Michael;Jordt, Sven-Eric
气道中的感觉神经元对威胁气道功能和完整性的反应性化学物质做出精细的反应。鼻三叉神经末梢对污染空气和氧化应激过程中形成的氧化剂以及工业和家庭事故中经常释放的氯特别敏感。氧化激活气道神经元引起呼吸抑制、鼻塞、打喷嚏、咳嗽和疼痛。虽然化学感觉气道反射通常具有保护作用，但在患有鼻炎和哮喘等炎症性气道疾病的患者中，可能会引起严重的并发症。在这里，我们发现次氯酸盐，氯的氧化介质和过氧化氢，一种活性氧，激活Ca2+内流和膜电流在氧化剂敏感的化学感觉神经元亚群。这些反应在缺乏TRPA1（瞬时受体电位（TRP）基因家族的一种离子通道）的小鼠的神经元中不存在。在原代感觉神经元和异源细胞中，次氯酸盐和过氧化氢强烈激活TRPA1通道。在呼吸功能测试中，Trpa1（-/-）小鼠在次氯酸盐和过氧化氢诱导的呼吸抑制以及氧化剂诱导的疼痛行为减少方面表现出严重缺陷。我们的研究结果表明，TRPA1是感觉神经元中的氧化传感器，在体外和体内启动神经元兴奋和随后的生理反应。
Sensory neurons in the airways are finely tuned to respond to reactive chemicals threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca2+ influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1(-/-) mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo.