The effects of pyrethroid insecticides on coloned and expressed vertebrate and invertebrate sodium channels

Pyrethroid insecticides bind to a unique site on voltage-dependent sodium channels and prolong sodium currents, leading to repetitive bursts of action potentials or use-dependent nerve block. The goal of this dissertation was to characterize the site and mode of action of pyrethroids on cloned sodium channel isoforms expressed in Xenopus oocytes. To determine if heterologously expressed sodium channels provide a viable system for studying pyrethroid mode of action, I injected synthetic mRNA encoding the rat brain IIa (rBIIa) sodium channel ;Pyrethroids also modified sodium currents carried by rat sensory nervous system (rSNS) sodium channels expressed in oocytes. The rSNS sodium channels displayed increased threshold sensitivity to the Type II pyrethroid cypermethrin compared to expressed rBIIa + r;Voltage-sensitive sodium channels (Vssc1) of the house fly (Musca domestica) were expressed in oocytes either alone or in combination with the tipE gene product of Drosophila melanogaster. The tipE gene product significantly enhanced the expression of Vssc1. Pyrethroids prolonged the sodium current carried by Vssc1/tipE sodium channels. Introduction of a single amino acid substitution associated with the kdr (knockdown resistance to pyrethroids) trait into the Vssc1 cDNA resulted in channels with reduced functional sensitivity to cismethrin. This result demonstrated that this single amino acid substitution is sufficient to account for the kdr resistance trait.