Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids.
Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids.
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DOI：
10.1016/j.neuro.2015.02.001
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发表时间：
2015-03
期刊：
影响因子：
3.4
通讯作者：
Dong, Ke
中科院分区：
文献类型：
--
作者：
Rinkevich, Frank D.;Du, Yuzhe;Tolinski, Josh;Ueda, Atsushi;Wu, Chun-Fang;Zhorov, Boris S.;Dong, Ke
电压门控钠通道（Nav 通道）对于神经系统中的电信号传导至关重要，也是杀虫剂 DDT 和拟除虫菊酯的主要目标。在果蝇中，除了典型的 Nav 通道 Para（也称为 DmNav）之外，还有一个类似钠通道的阳离子通道，称为 DSC1（果蝇钠通道 1）。 DmNav (parats) 中的温度敏感麻痹突变赋予对 DDT 和拟除虫菊酯的抗性，而 DSC1 敲除果蝇表现出对拟除虫菊酯的敏感性增强。为了进一步确定 DmNav 和 DSC1 通道在 DDT 和拟除虫菊酯神经毒理学中的作用和相互作用，我们通过将 parats1 等位基因（携带 I265N 突变）引入 DSC1 敲除系中，生成了 DmNav/DSC1 双突变系。我们证实，I265N 突变降低了非洲爪蟾卵母细胞中表达的 DmNav 变体对两种拟除虫菊酯、氯菊酯和溴氰菊酯的敏感性。计算机模型预测 I265N 突变通过变构改变 DmNav 通道上的第二个拟除虫菊酯受体位点而赋予拟除虫菊酯抗性。此外，我们发现parats1突变果蝇中I265N介导的拟除虫菊酯抗性在parats1;DSC1−/−双突变果蝇中几乎完全消除。然而，出乎意料的是，与对照果蝇（w1118A）相比，DSC1 敲除果蝇对 DDT 的敏感性较低，并且与 DSC1 敲除或 parats1 突变体相比，parats1;DSC1−/− 双突变果蝇对 DDT 的抵抗力更强。我们的研究结果揭示了 DmNav 和 DSC1 通道在 DDT 与拟除虫菊酯的神经毒理学中的不同作用，并暗示使用 DSC1 通道阻滞剂或修饰剂来管理拟除虫菊酯耐药性的令人兴奋的可能性。
Voltage-gated sodium channels (Nav channels) are critical for electrical signaling in the nervous system and are the primary targets of the insecticides DDT and pyrethroids. In Drosophila melanogaster, besides the canonical Nav channel, Para (also called DmNav), there is a sodium channel-like cation channel called DSC1 (Drosophila sodium channel 1). Temperature-sensitive paralytic mutations in DmNav (parats) confer resistance to DDT and pyrethroids, whereas DSC1 knockout flies exhibit enhanced sensitivity to pyrethroids. To further define the roles and interaction of DmNav and DSC1 channels in DDT and pyrethroid neurotoxicology, we generated a DmNav/DSC1 double mutant line by introducing a parats1 allele (carrying the I265N mutation) into a DSC1 knockout line. We confirmed that the I265N mutation reduced the sensitivity to two pyrethroids, permethrin and deltamethrin of a DmNav variant expressed in Xenopus oocytes. Computer modeling predicts that the I265N mutation confers pyrethroid resistance by allosterically altering the second pyrethroid receptor site on the DmNav channel. Furthermore, we found that I265N-mediated pyrethroid resistance in parats1 mutant flies was almost completely abolished in parats1;DSC1−/− double mutant flies. Unexpectedly, however, the DSC1 knockout flies were less sensitive to DDT, compared to the control flies (w1118A), and the parats1;DSC1−/− double mutant flies were even more resistant to DDT compared to the DSC1 knockout or parats1 mutant. Our findings revealed distinct roles of the DmNav and DSC1 channels in the neurotoxicology of DDT vs. pyrethroids and implicate the exciting possibility of using DSC1 channel blockers or modifiers in the management of pyrethroid resistance.
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4.1
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