Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels
Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels
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小鼠β-防御素 3，内源性和外源性钾通道的防御素抑制剂
DOI：
10.3390/molecules23061489
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发表时间：
2018-06-01
期刊：
影响因子：
4.6
通讯作者：
Wu, Yingliang
中科院分区：
文献类型：
--
作者：
Zhang, Yaoyun;Zhao, Yonghui;Wu, Yingliang
人类防御素最近被发现可以抑制钾通道，而钾通道是动物毒素的经典靶点。其他脊椎动物防御素是否也是钾通道抑制剂尚不清楚。在这项工作中，我们报道了小鼠β -防御素3 （mBD3）是内源性和外源性钾通道的新型抑制剂。结构分析表明，mBD3与人类Kv1.3通道敏感型人类纤维防御素2 （hBD2）最相似。然而，药理学分析表明，重组mBD3 （rmBD3）对小鼠和人的Kv1.3通道有微弱的抑制作用。与人β -防御素的药理特性不同，mBD3更有选择性地抑制小鼠Kv1.6和人KCNQ1/KCNE1通道，IC50值分别为0.6 +/- 0.4 μ M和1.2 +/- 0.8 μ M。位点定向诱变实验表明，小鼠Kv1.6通道细胞外孔区是rmBD3的相互作用位点。此外，mBD3对通道电导-电压关系曲线的影响较小，这表明mBD3可能结合小鼠Kv1.6通道的细胞外跨膜螺旋S1-S2连接子和/或S3-S4连接子。综上所述，这些发现不仅揭示了mBD3作为内源性和外源性钾通道的新型抑制剂，也为未来探讨mBD3- kv1.6通道相互作用在生理病理领域的作用提供了线索。
The human defensins are recently discovered to inhibit potassium channels, which are classical targets of the animal toxins. Whether other vertebrate defensins are potassium channel inhibitors remains unknown. In this work, we reported that the mouse beta-defensin 3 (mBD3) was a novel inhibitor of both endogenous and exogenous potassium channels. The structural analysis showed that mBD3 is the most identical to human Kv1.3 channel-sensitive human fi-defensin 2 (hBD2). However, the pharmacological profiles indicated that the recombinant mBD3 (rmBD3) weakly inhibited the mouse and human Kv1.3 channels. Different from the pharmacological features of human beta-defensins, mBD3 more selectively inhibited the mouse Kv1.6 and human KCNQ1/KCNE1 channels with IC50 values of 0.6 +/- 0.4 mu M and 1.2 +/- 0.8 mu M, respectively. The site directed mutagenesis experiments indicated that the extracellular pore region of mouse Kv1.6 channel was the interaction site of rmBD3. In addition, the minor effect on the channel conductance-voltage relationship curves implied that mBD3 might bind the extracellular transmembrane helices S1-S2 linker and/or S3-S4 linker of mouse Kv1.6 channel. Together, these findings not only revealed mBD3 as a novel inhibitor of both endogenous and exogenous potassium channels, but also provided a clue to investigate the role of mBD3-Kv1.6 channel interaction in the physiological and pathological field in the future.