The insect voltage-gated sodium channel as target of insecticides

Examination of the function, chemistry, and pharmacology of the voltage-gat ed insect sodium channel (ISC) reveals that the ISC closely resembles its v ertebrate counterpart in electrophysiology and ion conductance, primary str ucture and allocation of all functional domains, and its pharmacological di versity and flexibility exhibited by the occurrence of different allosteric ally coupled receptor-binding sites for various neurotoxicants. The toxicants include several groups of insecticides, namely DDT and its an alogues, pyrethroids, N-alkylamides, and dihydropyrazoles, which affect cha nnel gating and ion permeability. Despite their similarity, the insect and vertebrate channels are pharmacolo gically distinguishable, as revealed by the responsiveness of the heterolog ously expressed Drosophila para clone to channel modifiers and blockers and the occurrence of the insect-selective sodium channel neurotoxins derived from arachnid venoms presently used for the design of recombinant baculovir us-mediated selective bioinsecticides. The pharmacological specificity of the ISC may lead to the design of insect -selective toxicants, and its pharmacological flexibility may direct the us e of ISC insecticides for resistance management. Insecticide resistance [su ch as knockdown resistance (KDR)] is acquired by natural selection and oper ated by increased metabolism, channel mutagenesis, or both. The resistance issue can be dealt with in several ways. One is by simultane ous application of low doses of synergistic, allosterically coupled mixture s (thus delaying or preventing the onset of resistance). An alternative is to replace an insecticide to which resistance was acquired by channel mutat ion with a different ISC toxicant to which increased susceptibility was con ferred by the same mutation. Such a possibility was exemplified by a signif icant increase in susceptibility to N-alkylamides, as well as an insect-sel ective neurotoxin revealed by KDR insects. Third, both of these methods can be combined. Thus owing to its pharmacological uniqueness, the ISC may ser ve as a high-priority target for future selective and resistance-manageable insecticides.