Activation and Inhibition of Thermosensitive TRP Channels by Voacangine, an Alkaloid Present in Voacanga africana, an African Tree
Activation and Inhibition of Thermosensitive TRP Channels by Voacangine, an Alkaloid Present in Voacanga africana, an African Tree
复制标题
Voacangine（非洲树 Voacanga africana 中存在的一种生物碱）对热敏 TRP 通道的激活和抑制
DOI：
10.1021/np400885u
复制
发表时间：
2014
影响因子：
5.1
通讯作者：
and Tatsuo Watanabe
中科院分区：
文献类型：
--
作者：
Yuko Terada;Syunji Horie;Hiromitsu Takayama;Kunitoshi Uchida;Makoto;Tominaga;and Tatsuo Watanabe
Voacangine(1)是一种在非洲voacanga的根皮中发现的生物碱。我们之前的工作表明，1是一种新的瞬时受体电位香草样蛋白1型（TRPV1）拮抗剂。本研究考察了1对热敏TRP通道的激动剂和拮抗剂活性。通道活性主要通过表达TRP通道的HEK细胞和钙显像进行评估。本研究表明，1作为TRPV1和TRPM8的拮抗剂，但作为TRPA1的激动剂（EC50, 8 μM）。该化合物竞争性地阻断辣椒素与TRPV1的结合（IC50, 50 μM）。Voacangine(1)竞争性抑制薄荷醇与TRPM8的结合（IC50, 9 μM），但对icilin表现出非竞争性抑制（IC50, 7 μM）。此外，该化合物选择性地消除了化学激动剂诱导的TRPM8激活，并且不影响冷诱导的激活。在这些作用中，TRPM8抑制谱是独特而值得注意的，因为迄今为止还没有研究报道从天然来源获得的薄荷醇竞争性TRPM8抑制剂。此外，这是首次报道刺激选择性TRPM8拮抗剂。因此，1可能有助于开发一类新的刺激选择性TRPM8阻滞剂。
Voacangine (1) is an alkaloid found in the root bark ofVoacanga africana. Our previous work has suggested that1is a novel transient receptor potential vanilloid type 1 (TRPV1) antagonist. In this study, the agonist and antagonist activities of1were examined against thermosensitive TRP channels. Channel activity was evaluated mainly using TRP channel-expressing HEK cells and calcium imaging. Herein, it was shown that1acts as an antagonist for TRPV1 and TRPM8 but as an agonist for TRPA1 (EC50, 8 μM). The compound competitively blocked capsaicin binding to TRPV1 (IC50, 50 μM). Voacangine (1) competitively inhibited the binding of menthol to TRPM8 (IC50, 9 μM), but it showed noncompetitive inhibition against icilin (IC50, 7 μM). Moreover, the compound selectively abrogated chemical agonist-induced TRPM8 activation and did not affect cold-induced activation. Among these effects, the TRPM8 inhibition profile is unique and noteworthy, because to date no studies have reported a menthol competitive inhibitor of TRPM8 derived from a natural source. Furthermore, this is the first report of a stimulus-selective TRPM8 antagonist. Accordingly,1may contribute to the development of a novel class of stimulus-selective TRPM8 blockers.