Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress.
Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress.
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DOI：
10.1523/jneurosci.5369-07.2008
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发表时间：
2008-03-05
期刊：
影响因子：
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通讯作者：
Bevan S
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文献类型：
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作者：
Andersson DA;Gentry C;Moss S;Bevan S
瞬时受体电位A1(TRPA1)在一组伤害性感觉神经元中表达，在那里它作为环境刺激物(包括丙烯醛)和一些刺激性植物成分(如异硫氰酸烯丙酯和肉桂醛)的传感器。这些外源化合物通过半胱氨酸残基的共价修饰激活TRPA1。我们使用电生理学方法和细胞内钙离子浓度([Ca~(2+)]i)的测量表明，TRPA1被几类内源性硫代反应分子激活。TRPA1被过氧化氢(H_2O_2；EC_(50)，230μM)、内源性烯基醛(EC_(50)：4-羟基壬烯醛19.9μM、4-羟基己烯醛1.9μM、4-羟基己烯醛38.9μM)和环戊酮前列腺素J2(15-deoxy-Δ12，14-prostaglandin J2，15d-PGJ2，EC_(50)：5.6μM)激活。H_2O_2的作用被二硫苏糖醇逆转，表明H_2O_2通过促进二硫键的形成而起作用，而烯醛和15d-PGJ2的作用不被逆转，这表明这些试剂形成了Michael加合物。H_2O_2、天然产生的烯醛和15d-PGJ2作用于分离的大鼠和小鼠感觉神经元[~25%的大鼠背根神经节(DRG)和~50%的结状神经节神经元]，引起TRPA1表达神经元的去极化内向电流和[Ca~(2+)]i升高。在TRPA1-/-小鼠中，H_2O_2、烯醛和15d-PGJ2升高小鼠背根神经节神经元[Ca~(2+)]i的能力显著降低。此外，足底注射双氧水或15d-PGJ2在野生型小鼠中引起疼痛反应，但在TRPA1-/-小鼠中不引起。这些数据表明，氧化应激过程中产生的多种物质可以激活感觉神经元中表达的TRPA1。
Transient receptor potential A1 (TRPA1) is expressed in a subset of nociceptive sensory neurons where it acts as a sensor for environmental irritants, including acrolein, and some pungent plant ingredients such as allyl isothiocyanate and cinnamaldehyde. These exogenous compounds activate TRPA1 by covalent modification of cysteine residues. We have used electrophysiological methods and measurements of intracellular calcium concentration ([Ca2+]i) to show that TRPA1 is activated by several classes of endogenous thiolreactive molecules. TRPA1 was activated by hydrogen peroxide (H2O2; EC50, 230 μM), by endogenously occurring alkenyl aldehydes (EC50: 4-hydroxynonenal 19.9 μM, 4-oxo-nonenal 1.9 μM, 4-hydroxyhexenal 38.9 μM) and by the cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, EC50: 5.6 μM). The effect of H2O2 was reversed by treatment with dithiothreitol indicating that H2O2 acts by promoting the formation of disulfide bonds whereas the actions of the alkenyl aldehydes and 15d-PGJ2 were not reversed, suggesting that these agents form Michael adducts. H2O2 and the naturally occurring alkenyl aldehydes and 15d-PGJ2 acted on a subset of isolated rat and mouse sensory neurons [~25% of rat dorsal root ganglion (DRG) and ~50% of nodose ganglion neurons] to evoke a depolarizing inward current and an increase in [Ca2+]i in TRPA1 expressing neurons. The abilities of H2O2, alkenyl aldehydes and 15d-PGJ2 to raise [Ca2+]i in mouse DRG neurons were greatly reduced in neurons from trpa1-/- mice. Furthermore, intraplantar injection of either H2O2 or 15d-PGJ2 evoked a nocifensive/pain response in wild-type mice, but not in trpa1-/- mice. These data demonstrate that multiple agents produced during episodes of oxidative stress can activate TRPA1 expressed in sensory neurons.