Etodolac activates and desensitizes transient receptor potential ankyrin 1
Etodolac activates and desensitizes transient receptor potential ankyrin 1
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依托度酸激活瞬时受体电位锚蛋白 1 并使之脱敏
DOI：
10.1002/jnr.23274
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发表时间：
2013
期刊：
影响因子：
4.2
通讯作者：
Noguchi K
中科院分区：
文献类型：
--
作者：
Wang S;Dai Y;Kogure Y;Yamamoto S;Zhang W;Noguchi K
瞬时受体电位锚蛋白1（TRPA 1）通道是众所周知的环境刺激化合物，冷，和内源性促痛剂的传感器。TRPA 1在感觉神经元上表达，并参与疼痛调节。依托度酸是一种环氧合酶（考克斯）-2抑制剂，属于非甾体类抗炎药（NSAID）。最近的一项研究表明，依托度酸抑制异硫氰酸烯丙酯（AITC）诱导的异源HEK 293细胞和感觉神经元中的钙内流。为了研究依托度酸是否以及如何调节TRPA 1通道，我们将依托度酸应用于TRPA 1转染的HEK 293细胞或大鼠背根神经节（DRG）神经元，并使用全细胞膜片钳技术记录电流。我们发现，依托度酸在较高剂量可以激活，然后脱敏TRPA 1通道异源表达HEK 293细胞以及DRG神经元。依托度酸诱导的电流在半胱氨酸残基突变的人TRPA 1转染的HEK 293细胞中显著减弱。有趣的是，在临床使用中以药物血浆水平应用依托度酸不会诱导显著的TRPA 1电流，但在表达TRPA 1的HEK 293细胞中将随后的AITC诱导电流降低至25%。此外，在半胱氨酸突变细胞中未检测到依托度酸对TRPA 1的调节作用。这些数据表明依托度酸抗炎和镇痛临床作用的新机制，可能与其直接激活和随后通过半胱氨酸残基的共价修饰使TRPA 1脱敏有关。版权所有2013作者。《神经科学研究杂志》（Journal of Neuroscience Research）由Wiley Periodicals，Inc.出版。
The transient receptor potential ankyrin 1 (TRPA1) channel is well known as a sensor to environmental irritant compounds, cold, and endogenous proalgesic agents. TRPA1 is expressed on sensory neurons and is involved in pain modulation. Etodolac is a cyclooxygenase (COX)‐2 inhibitor that belongs to the class of nonsteroidal anti‐inflammatory drugs (NSAIDs). A recent study indicates that etodolac inhibits allyl isothiocyanate (AITC)‐induced calcium influx in heterologous HEK293 cells and sensory neurons. To examine whether and how etodolac modulates the TRPA1 channels, we applied etodolac to TRPA1‐transfected HEK293 cells or rat dorsal root ganglion (DRG) neurons and recorded the currents using the whole‐cell patch clamp technique. We found that etodolac at higher doses could activate and then desensitize TRPA1 channels in heterologous expressing HEK293 cells as well as in DRG neurons. The etodolac‐induced currents were significantly attenuated in cysteine residues mutated human TRPA1‐transfected HEK293 cells. Interestingly, application of etodolac at drug plasma levels in clinical usage did not induce significant TRPA1 currents but reduced the subsequent AITC‐induced currents to 25% in HEK293 cells expressing TRPA1. Moreover, no modulatory effect of etodolac on TRPA1 was detected in the cysteine mutant cells. These data indicate a novel mechanism of the anti‐inflammatory and analgesic clinical effects of etodolac, which may be involved with its direct activation and the subsequent desensitization of TRPA1 through the covalent modification of cysteine residues. © 2013 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.