State-Dependent Actions Of Sodium Channel Inhibitor Insecticides On Mammalian Voltage-Gated Sodium Channels

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Sodium channel inhibitor insecticides are an emerging class of neurotoxic insect control agents that selectively inhibit voltage-gated sodium channels at membrane potentials that promote slow sodium channel inactivation. Metaflumizone, a newly-commercialized insecticide in the animal health market, causes state-dependent inhibition of insect sodium channels. The goal of this dissertation was to investigate the state-dependent effects of metaflumizone; indoxacarb, the only other commercialized compound in this insecticide class; DCJW, the bioactivation metabolite of indoxacarb in insects; and RH-3421 and RH-4841, two experimental insecticides, on mammalian sodium channels using the Xenopus laevis oocyte expression system. The two-electrode voltage clamp technique was used to measure sodium currents from unfertilized Xenopus frog eggs injected with rat Nav1.4 sodium channel and auxiliary [beta]1-subunit cRNA. Characterization of slow inactivation revealed that it is a heterogeneous biophysical process composed on multiple conformational states that are kinetically, functionally, and structurally distinct. Metaflumizone shifted the voltage dependence of slow inactivation in the direction of hyperpolarization and selectively inhibited mammalian sodium channels at membrane potentials that facilitated slow inactivation. However, perfusion of metaflumizone at a hyperpolarized potential caused a depolarizing shift in the voltage dependence of activation and selectively antagonized use-dependent lidocaine inhibition. These results imply that metaflumizone binds to sodium channels in the resting and fast-inactivated state in a manner that is distinct from other compounds in this insecticide class. I substituted alanine, cysteine, or lysine for residue V787 in DII-S6 of Nav1.4 channels to test the hypothesis that the extent of insecticide inhibition is directly related to the availability of slow-inactivated sodium channels. Substitutions at V787 had residue- and compound-specific effects on the actions of sodium channel inhibitor insecticides that were independent of mutation-induced changes in slow inactivation. These results imply that V787 is part of or in close proximity to the binding site for sodium channel inhibitor insecticides on mammalian voltage-gated sodium channels, which may not be identical for all members of this insecticide class.

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Soderlund, David Matthew

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Weiland, Gregory A.
Oswald, Robert Edward

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Environmental Toxicology

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Ph. D., Environmental Toxicology

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Doctor of Philosophy

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dissertation or thesis

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