Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids.
Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids.
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DOI：
10.1016/j.neuro.2016.06.009
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发表时间：
2017-05
期刊：
影响因子：
3.4
通讯作者：
Dong K
中科院分区：
文献类型：
--
作者：
Chen M;Du Y;Nomura Y;Zhu G;Zhorov BS;Dong K
拟除虫菊酯类杀虫剂通过延长电压门控钠通道的开放而发挥毒性作用。来自节肢动物害虫和疾病媒介的20多个钠通道突变已被证实赋予拟除虫菊酯抗性。这些突变在阐明拟除虫菊酯和钠通道之间的分子相互作用方面具有价值，包括鉴定两个拟除虫菊酯受体位点。以前，在抗DDT和溴氰菊酯的果蝇突变体中发现了两个丙氨酸到缬氨酸的取代，一个在孔螺旋IIIP 1中，另一个在结构域III中连接S4和S5的接头螺旋（IIIL 45）中（在苯基苄醇位置上具有α-氰基的II型拟除虫菊酯，其在I型拟除虫菊酯中缺乏），但它们在靶位点介导的杀虫剂抗性中的作用尚未在功能上得到证实。在这项研究中，我们功能性地研究了两个突变的蟑螂钠通道表达非洲爪蟾卵母细胞。这两种突变导致去极化位移的电压依赖性激活，赋予DDT的阻力，也耐两种I型拟除虫菊酯几乎废除的尾电流诱导的I型拟除虫菊酯。相比之下，无论是突变降低的幅度诱导的II型拟除虫菊酯，溴氰菊酯或氯氰菊酯的尾电流。然而，这两种突变都加速了II型拟除虫菊酯诱导的尾电流的衰减，而II型拟除虫菊酯诱导的尾电流通常衰减非常缓慢。这些结果为I型和II型拟除虫菊酯对钠通道不同作用的分子基础提供了新的见解。计算机建模预测，这两种突变可能会变构影响拟除虫菊酯的结合。
Pyrethroid insecticides exert toxic effects by prolonging the opening of voltage-gated sodium channels. More than 20 sodium channel mutations from arthropod pests and disease vectors have been confirmed to confer pyrethroid resistance. These mutations have been valuable in elucidating the molecular interaction between pyrethroids and sodium channels, including identification of two pyrethroid receptor sites. Previously, two alanine to valine substitutions, one in the pore helix IIIP1 and the other in the linker-helix connecting S4 and S5 in domain III (IIIL45), were found in Drosophila melanogaster mutants that are resistant to DDT and deltamethrin (a type II pyrethroid with an α-cyano group at the phenylbenzyl alcohol position, which is lacking in type I pyrethroids), but their role in target-site-mediated insecticide resistance has not been functionally confirmed. In this study, we functionally examined the two mutations in cockroach sodium channels expressed in Xenopus laevis oocytes. Both mutations caused depolarizing shifts in the voltage dependence of activation, conferred DDT resistance and also resistance to two Type I pyrethroids by almost abolishing the tail currents induced by Type I pyrethroids. In contrast, neither mutation reduced the amplitude of tail currents induced by the Type II pyrethroids, deltamethrin or cypermethrin. However, both mutations accelerated the decay of Type II pyrethroid-induced tail currents, which normally decay extremely slowly. These results provided new insight into the molecular basis of different actions of Type I and Type II pyrethroids on sodium channels. Computer modeling predicts that both mutations may allosterically affect pyrethroid binding.
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