Synthetic pyrethroids are an important class of neurotoxic insecticides used worldwide in agriculture and public health. Pyrethroids cause toxic effects in vertebrate nerves and muscles by modifying the normal function of voltage-sensitive sodium channels. Sodium channels exist in multiple isoforms that exhibit differential tissue distribution and developmental regulation and are encoded by members of a multigene family. Previous studies of pyrethroid action have not considered the differential sensitivity of sodium channel isoforms as a determining factor in the toxicity of these compounds. The overall objectives of the proposed research are to test the hypotheses that vertebrate sodium channel isoforms exhibit differential sensitivity to synthetic pyrethroids and that these differences in sensitivity are important determinants of the nature and severity of toxicological responses to pyrethroid exposure. Specific experimental goals are: (1) to define the actions of pyrethroid insecticides on cloned rat sodium channel isoforms expressed in Xenopus oocytes; (2) to correlate the effects of pyrethroids on sodium channel isoforms with acute and chronic neurotoxic effects; (3) to compare the actions of pyrethroids on homologous rat and human sodium channel isoforms expressed in oocytes; and (4) to map the structural determinants of differential pyrethroid sensitivity among sodium channel isoforms by the construction, heterologous functional expression and pharmacological characterization of chimeric and specifically mutated sodium channels. Cloned sodium channel isoforms will be expressed in Xenopus oocytes and the actions of pyrethroids on the channels will be assessed under voltage clamp. Results of these studies will define the role of different sodium channel isoforms in pyrethroid toxicity. Comparisons of rat and human sodium channel isoforms will determine whether rat isoforms are valid models for the sensitivity of homologous human isoforms to pyrethroids. Studies with chimeric and mutated isoforms will identify channel domains that determine pyrethroid sensitivity and will contribute to knowledge of structure-function relationships for sodium channels.