Kv1.3 potassium channel-blocking toxin Ctri9577, novel gating modifier of Kv4.3 potassium channel from the scorpion toxin family
Kv1.3 potassium channel-blocking toxin Ctri9577, novel gating modifier of Kv4.3 potassium channel from the scorpion toxin family
复制标题
Kv1.3 钾通道阻断毒素 Ctri9577，来自蝎子毒素家族的 Kv4.3 钾通道的新型门控修饰剂
DOI：
10.1016/j.bbrc.2014.01.094
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发表时间：
2014-02-14
影响因子：
3.1
通讯作者：
Wu, Yingliang
中科院分区：
文献类型：
--
作者：
Xie, Chang;Li, Tian;Wu, Yingliang
蝎毒素Ctri 9577是Kv1.3钾通道阻断剂，是Kv4.x钾通道阻断剂α-KTx 15亚家族的新成员。然而，Ctri 9577对Kv4.x通道的药理学功能仍然未知。发现蝎毒素Ctri 9577有效地抑制Kv4.3通道电流，IC 50值为1.34 +/- 0.03 μ M。与蝎毒素作为识别通道胞外孔入口的阻断剂的机制不同，Ctri 9577是一种新型的门控修饰剂，影响Kv4.3通道的激活、稳态失活和失活后的恢复过程的电压依赖性。然而，Ctri 9755，作为一个有效的Kv1.3通道阻断剂，被发现不影响电压依赖性的激活Kv1.3通道。有趣的是，药理学实验表明，1 μ M Ctri 9755对Kv4.1和Kv4.2通道电流的抑制较小。与蜘蛛毒素的经典门控修饰剂类似，通过诱变实验显示Ctri 9577与跨膜S3和S4螺旋结构域之间的接头相互作用。据我们所知，Ctri 9577是蝎毒素家族中第一个钾通道的门控调节剂，也是第一个同时作为门控调节剂和阻断剂的蝎毒素。这些发现进一步强调了钾通道特异性蝎毒素的结构和功能多样性。(C)2014 Elsevier Inc. All rights reserved.
Scorpion toxin Ctri9577, as a potent Kv1.3 channel blocker, is a new member of the alpha-KTx15 subfamily which are a group of blockers for Kv4.x potassium channels. However, the pharmacological function of Ctri9577 for Kv4.x channels remains unknown. Scorpion toxin Ctri9577 was found to effectively inhibit Kv4.3 channel currents with IC50 value of 1.34 +/- 0.03 mu M. Different from the mechanism of scorpion toxins as the blocker recognizing channel extracellular pore entryways, Ctri9577 was a novel gating modifier affecting voltage dependence of activation, steady-state inactivation, and the recovery process from the inactivation of Kv4.3 channel. However, Ctri9755, as a potent Kv1.3 channel blocker, was found not to affect voltage dependence of activation of Kv1.3 channel. Interestingly, pharmacological experiments indicated that 1 mu M Ctri9755 showed less inhibition on Kv4.1 and Kv4.2 channel currents. Similar to the classical gating modifier of spider toxins, Ctri9577 was shown to interact with the linker between the transmembrane S3 and S4 helical domains through the mutagenesis experiments. To the best of our knowledge, Ctri9577 was the first gating modifier of potassium channels among scorpion toxin family, and the first scorpion toxin as both gating modifier and blocker for different potassium channels. These findings further highlighted the structural and functional diversity of scorpion toxins specific for the potassium channels. (C) 2014 Elsevier Inc. All rights reserved.