Charge substitutions at the voltage-sensing module of domain III enhance actions of site-3 and site-4 toxins on an insect sodium channel

文献类型： 外文期刊

第一作者： Zhu, Qing

作者： Zhu, Qing;Zhu, Qing;Du, Yuzhe;Nomura, Yoshiko;Dong, Ke;Gao, Rong;Cang, Zixuan;Wei, Guo-Wei;Gordon, Dalia;Gurevitz, Michael;Groome, James;Dong, Ke;Du, Yuzhe;Gordon, Dalia

作者机构：

关键词： Insect sodium channel; Scorpion alpha-toxin; Scorpion beta-toxin; Homology modeling; Mutagenesis; Electrophysiology

期刊名称：INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY （ 影响因子：4.714； 五年影响因子：4.953 ）

ISSN： 0965-1748

年卷期： 2021 年 137 卷

页码：

收录情况： SCI

摘要： Scorpion alpha-toxins bind at the pharmacologically-defined site-3 on the sodium channel and inhibit channel inactivation by preventing the outward movement of the voltage sensor in domain IV (IVS4), whereas scorpion beta-toxins bind at site-4 on the sodium channel and enhance channel activation by trapping the voltage sensor of domain II (IIS4) in its outward position. However, limited information is available on the role of the voltage-sensing modules (VSM, comprising S1-S4) of domains I and III in toxin actions. We have previously shown that charge reversing substitutions of the innermost positively-charged residues in IIIS4 (R4E, R5E) increase the activity of an insect-selective site-4 scorpion toxin, Lqh-dprIT(3)-c, on BgNa(v)1-1a, a cockroach sodium channel. Here we show that substitutions R4E and R5E in IIIS4 also increase the activity of two site-3 toxins, Lqh alpha IT from Leiurusquinquestriatus hebraeus and insect-selective Av3 from Anemonia viridis. Furthermore, charge reversal of either of two conserved negatively-charged residues, D1K and E2K, in IIIS2 also increase the action of the site-3 and site-4 toxins. Homology modeling suggests that S2-D1 and S2-E2 interact with S4-R4 and S4-R5 in the VSM of domain III (III-VSM), respectively, in the activated state of the channel. However, charge swapping between S2-D1 and S4-R4 had no compensatory effects on gating or toxin actions, suggesting that charged residue interactions are complex. Collectively, our results highlight the involvement of III-VSM in the actions of both site 3 and site 4 toxins, suggesting that charge reversing substitutions in III-VSM allosterically facilitate IIS4 or IVS4 voltage sensor trapping by these toxins.

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