Molecular basis of the inhibition of the fast inactivation of voltage-gated sodium channel Nav1.5 by tarantula toxin Jingzhaotoxin-II
Molecular basis of the inhibition of the fast inactivation of voltage-gated sodium channel Nav1.5 by tarantula toxin Jingzhaotoxin-II
复制标题
狼蛛毒素京兆毒素-II抑制电压门控钠通道Nav1.5快速失活的分子基础
DOI：
10.1016/j.peptides.2015.03.012
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发表时间：
2015-06-01
期刊：
影响因子：
3
通讯作者：
Liu, Zhonghua
中科院分区：
文献类型：
--
作者：
Huang, Ying;Zhou, Xi;Liu, Zhonghua
Jingzhaotoxin-II（JZTX-II）是来自中国狼蛛Chilobrachysjingzhao毒的32个氨基酸残基的肽，优先抑制大鼠心肌细胞电压门控钠通道（VGSCs）的快速失活。在本研究中，我们阐明JZTX-II抑制hNav1.5，主要分布在人心肌细胞的VGSC亚型的作用机制。在测试的四种VGSC亚型中，hNav1.5对JZTX-II最敏感（EC 50 = 125 +/- 4 nM）。虽然JZTX-II对hNav1.5传导的残余电流的稳态失活几乎没有影响，但它引起了10 mV的激活超极化移位。此外，JZTX-II增加了hNav1.5通道的恢复速率，这将导致从失活到关闭状态的较短转变。JZTX-II通过极端去极化从毒素通道复合物中解离，随后在复极化时反弹到通道中。突变分析表明，结构域IV（DIV）电压传感器结构域（VSD）是JZTX-II与hNav1.5结合的关键，并且位于hNav1.5 DIV的S1-S2和S3-S4胞外环的一些突变相加地降低了hNav1.5的毒素敏感性。我们的数据确定了JZTX-II抑制hNav1.5的潜在机制，类似于蝎子α-毒素，涉及与神经毒素受体位点3的结合。(C)2015爱思唯尔公司All rights reserved.
Jingzhaotoxin-II (JZTX-II) is a 32-residue peptide from the Chinese tarantula Chilobrachysjingzhao venom, and preferentially inhibits the fast inactivation of the voltage-gated sodium channels (VGSCs) in rat cardiac myocytes. In the present study, we elucidated the action mechanism of JZTX-II inhibiting hNav1.5, a VGSC subtype mainly distributed in human cardiac myocytes. Among the four VGSC subtypes tested, hNav1.5 was the most sensitive to JZTX-II (EC50 = 125 +/- 4 nM). Although JZTX-II had little or no effect on steady-state inactivation of the residual currents conducted by hNav1.5, it caused a 10 mV hyperpolarized shift of activation. Moreover, JZTX-II increased the recovery rate of hNav1.5 channels, which should lead to a shorter transition from the inactivation to closed state. JZTX-II dissociated from toxin-channel complex via extreme depolarization and subsequently rebound to the channel upon repolarization. Mutagenesis analyses showed that the domain IV (DIV) voltage-sensor domain (VSD) was critical for JZTX-II binding to hNav1.5 and some mutations located in S1-S2 and S3-S4 extracellular loops of hNav1.5 DIV additively reduced the toxin sensitivity of hNav1.5. Our data identified the mechanism underlying JZTX-II inhibiting hNav1.5, similar to scorpion a-toxins, involving binding to neurotoxin receptor site 3. (C) 2015 Elsevier Inc. All rights reserved.