Warmke J W, Reenan R A, Wang P, Qian S, Arena J P, Wang J, Wunderler D, Liu K, Kaczorowski G J, Van der Ploeg L H, Ganetzky B, Cohen C J
Department of Genetics and Molecular Biology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
J Gen Physiol. 1997 Aug;110(2):119-33. doi: 10.1085/jgp.110.2.119.
The Drosophila para sodium channel alpha subunit was expressed in Xenopus oocytes alone and in combination with tipE, a putative Drosophila sodium channel accessory subunit. Coexpression of tipE with para results in elevated levels of sodium currents and accelerated current decay. Para/TipE sodium channels have biophysical and pharmacological properties similar to those of native channels. However, the pharmacology of these channels differs from that of vertebrate sodium channels: (a) toxin II from Anemonia sulcata, which slows inactivation, binds to Para and some mammalian sodium channels with similar affinity (Kd congruent with 10 nM), but this toxin causes a 100-fold greater decrease in the rate of inactivation of Para/TipE than of mammalian channels; (b) Para sodium channels are >10-fold more sensitive to block by tetrodotoxin; and (c) modification by the pyrethroid insecticide permethrin is >100-fold more potent for Para than for rat brain type IIA sodium channels. Our results suggest that the selective toxicity of pyrethroid insecticides is due at least in part to the greater affinity of pyrethroids for insect sodium channels than for mammalian sodium channels.
果蝇para钠通道α亚基单独在非洲爪蟾卵母细胞中表达，以及与tipE（一种假定的果蝇钠通道辅助亚基）共同表达。tipE与para共同表达会导致钠电流水平升高且电流衰减加速。Para/TipE钠通道具有与天然通道相似的生物物理和药理学特性。然而，这些通道的药理学与脊椎动物钠通道不同：（a）来自沟迎风海葵的毒素II可减缓失活，它以相似的亲和力（解离常数约为10 nM）与Para及一些哺乳动物钠通道结合，但该毒素导致Para/TipE失活速率的降低幅度比哺乳动物通道大100倍；（b）Para钠通道对河豚毒素阻断的敏感性高10倍以上；（c）拟除虫菊酯类杀虫剂氯菊酯对Para的修饰效力比对大鼠脑IIA型钠通道高100倍以上。我们的结果表明，拟除虫菊酯类杀虫剂的选择性毒性至少部分归因于拟除虫菊酯对昆虫钠通道的亲和力比对哺乳动物钠通道的亲和力更高。
