Bloomquist J R, Soderlund D M
Department of Entomology, New York State Agricultural Experiment Station, Cornell University, Geneva 14456.
Mol Pharmacol. 1988 May;33(5):543-50.
The effects of saturating concentrations of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] and the pyrethroid insecticides cismethrin and deltamethrin on alkaloid-dependent activation of the voltage-sensitive sodium channel were studied using measurements of 22Na+ uptake into mouse brain synaptosomes. In survey experiments, these compounds enhanced sodium uptake stimulated by veratridine and batrachotoxin, but inhibited uptake stimulated by aconitine. Concentration response curves for aconitine run in the absence and presence of 10 microM cismethrin demonstrated that the inhibition was noncompetitive. This unanticipated inhibitory effect of insecticides on aconitine-dependent sodium uptake suggests a possible overlap or negative allosteric coupling between the binding sites for insecticides and aconitine and reveals unique characteristics of the action of aconitine that are not shared by veratridine and batrachotoxin. More detailed studies of the effects of insecticides on veratridine- or batrachotoxin-stimulated uptake found small insecticide-dependent increases in the potency of these activators. In addition to this effect, DDT and deltamethrin also enhanced maximal uptake stimulated by veratridine. Possible mechanisms underlying these effects of insecticides on alkaloid-dependent uptake are discussed in light of a qualitative model formulated from these results and previous biochemical and electrophysiological studies. Additional experiments were designed to assess the interactions of insecticides and toxin II of the sea anemone Anemonia sulcata (ATX II) as modifiers of alkaloid-dependent uptake. DDT and ATX II acted synergistically to increase uptake stimulated by veratridine. Moreover, DDT shifted the potency of ATX II for enhancing veratridine-dependent uptake to 5-fold lower concentrations. In contrast, DDT and subsaturating concentrations of ATX II acted independently in their enhancement of sodium channel activation by batrachotoxin. Mutually exclusive effects on veratridine-dependent uptake were observed when cismethrin was co-applied with ATX II. However, independent effects of cismethrin and ATX II were found with aconitine-modified channels, in that cismethrin was able to inhibit ATX II-enhanced aconitine-dependent sodium flux. Thus, the interactions between insecticides and ATX II as modifiers of alkaloid-dependent uptake are complex and depend on the insecticide-activator combination under study.
利用对小鼠脑突触体摄取(^{22}Na^+)的测量，研究了饱和浓度的滴滴涕（1,1,1 - 三氯 - 2,2 - 双（对氯苯基）乙烷）以及拟除虫菊酯类杀虫剂顺式氯菊酯和溴氰菊酯对生物碱依赖性电压敏感钠通道激活的影响。在调查实验中，这些化合物增强了藜芦碱和蛙毒素刺激的钠摄取，但抑制了乌头碱刺激的摄取。在不存在和顺式氯菊酯（10μM）存在的情况下对乌头碱的浓度 - 反应曲线表明，这种抑制是非竞争性的。杀虫剂对乌头碱依赖性钠摄取的这种意外抑制作用表明，杀虫剂和乌头碱的结合位点之间可能存在重叠或负变构偶联，并揭示了乌头碱作用的独特特征，这些特征是藜芦碱和蛙毒素所不具备的。对杀虫剂对藜芦碱或蛙毒素刺激的摄取的影响进行的更详细研究发现，这些激活剂的效力有小的杀虫剂依赖性增加。除了这种作用外，滴滴涕和溴氰菊酯还增强了藜芦碱刺激的最大摄取。根据从这些结果以及先前生化和电生理研究得出的定性模型，讨论了杀虫剂对生物碱依赖性摄取的这些作用的潜在机制。设计了额外的实验来评估杀虫剂与海葵沟海葵毒素II（ATX II）作为生物碱依赖性摄取调节剂的相互作用。滴滴涕和ATX II协同作用以增加藜芦碱刺激的摄取。此外，滴滴涕将ATX II增强藜芦碱依赖性摄取的效力转移到低5倍的浓度。相反，滴滴涕和亚饱和浓度的ATX II在增强蛙毒素对钠通道的激活方面独立起作用。当顺式氯菊酯与ATX II共同应用时，观察到对藜芦碱依赖性摄取的相互排斥作用。然而，在乌头碱修饰的通道中发现顺式氯菊酯和ATX II的独立作用，因为顺式氯菊酯能够抑制ATX II增强的乌头碱依赖性钠通量。因此，杀虫剂和ATX II作为生物碱依赖性摄取调节剂之间的相互作用是复杂的，并且取决于所研究的杀虫剂 - 激活剂组合。
