A Potent and Site-Selective Agonist of TRPA1.
A Potent and Site-Selective Agonist of TRPA1.
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DOI：
10.1021/jacs.5b10162
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发表时间：
2015-12
影响因子：
15
通讯作者：
Junichiro Takaya;K. Mio;T. Shiraishi;Tatsuki Kurokawa;Shinya Otsuka;Y. Mori;M. Uesugi
中科院分区：
文献类型：
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作者：
Junichiro Takaya;K. Mio;T. Shiraishi;Tatsuki Kurokawa;Shinya Otsuka;Y. Mori;M. Uesugi
TRPA1是瞬时受体电位（TRP）阳离子通道家族的成员，主要在感觉神经元上表达。这种化学传感器是通过多种半胱氨酸残基的共价修饰激活的，其中包括异硫氰酸烯丙酯（AITC），一种芥末的辛辣成分。本研究报道了通过筛选1657个亲电分子发现的TRPA1的强效和选择性激动剂。为了验证击中分子的作用模式，我们注意到一种新的TRPA1选择性激动剂JT010（分子1），它通过共价和位点选择性结合Cys621 （EC50 = 0.65 nM）打开TRPA1通道。结果表明，单次修饰Cys621就足以打开TRPA1通道。本文描述的TRPA1选择性探针可能有助于进一步研究TRPA1活化的机制。
TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation.