Department of Veterinary Pharmacology, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan.
J Mol Neurosci. 2013 Nov;51(3):754-62. doi: 10.1007/s12031-013-0060-2. Epub 2013 Jul 20.
The transient receptor potential A1 (TRPA1) receptor is a member of the TRP family and an excitatory nonselective cation channel. An increasing body of evidence suggests that TRPA1 acts as a nociceptor for various chemicals and physical stimuli. Thus, many TRPA1 antagonists have been developed as analgesic agents. Recently, we found that AP18, a mammalian TRPA1 antagonist, does not inhibit heterologously expressed western clawed frog TRPA1 (fTRPA1). Here, we show that fTRPA1 is also insensitive to A967079, one of the most potent mammalian TRPA1 antagonists. Neither heterologously nor endogenously expressed fTRPA1 was inhibited by A967079 upon activation by TRPA1 agonists. Mutant channel analyses revealed that two specific amino acid residues located within the putative fifth transmembrane domain were involved in the inhibitory action of A967079. Our findings and previous reports based on species differences in the sensitivity to TRPA1 antagonists provide novel insights into the structure-function relationship of TRPA1 and supply useful information in the search for new analgesic medicines targeting TRPA1.
瞬时受体电位 A1（TRPA1）受体是 TRP 家族的成员，也是一种兴奋性非选择性阳离子通道。越来越多的证据表明，TRPA1 作为各种化学物质和物理刺激的伤害感受器。因此，许多 TRPA1 拮抗剂已被开发为镇痛药。最近，我们发现哺乳动物 TRPA1 拮抗剂 AP18 不能抑制异源表达的西方爪蟾 TRPA1（fTRPA1）。在这里，我们表明 fTRPA1 对哺乳动物 TRPA1 拮抗剂中最有效的之一 A967079 也不敏感。TRPA1 激动剂激活时，A967079 既不抑制异源表达的也不抑制内源性表达的 fTRPA1。突变通道分析表明，位于假定的第五跨膜域内的两个特定氨基酸残基参与了 A967079 的抑制作用。我们的发现和以前基于对 TRPA1 拮抗剂敏感性的物种差异的报告提供了 TRPA1 的结构-功能关系的新见解，并为寻找针对 TRPA1 的新型镇痛药提供了有用的信息。
