Pyrethroid insecticides and DDT modify alkaloid-dependent sodium channel activation and its enhancement by sea...

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.