Pyrazoline-type insecticides (PTIs) are a new class of insecticides exemplified by indoxacarb, the first compound of the class registered for commercial use in the United States. PTIs exert their neurotoxic effects in insects by selectively blocking sodium channels in depolarized cells. PTIs also selectively block mammalian sodium channels at membrane potentials that promote slow sodium channel inactivation. This effect is similar in many respects to the state-dependent sodium channel block caused by several classes of therapeutic drugs (e.g., local anesthetics, antiarrhythmics, anticonvulsants, neuroprotectants and analgesics) that bind to the """"""""local anesthetic receptor"""""""" site of sodium channels. As a result, the local anesthetic receptor has been implicated indirectly as the site of PTI action. The proposed research will test the hypothesis that PTIs block sodium channels by binding to the local anesthetic receptor site of slow-inactivated sodium channels. Specific experimental aims for the proposed funding period are: (1) to define the actions of PTIs on cloned rat sodium channel isoforms and subunit combinations expressed in Xenopus oocytes;(2) to elucidate the mechanism of voltage-dependent sodium channel block by PTIs;and (3) to map the structural determinants of PTI binding to sodium channels by site-directed mutagenesis. Cloned sodium channel isoforms will be expressed in Xenopus oocytes and the actions of PTIs on expressed channels will be assessed using electrophysiological recordings of sodium currents under voltage-clamp conditions. Results of these studies will define the differential sensitivity of sodium channel isoforms to PTIs, elucidate the mechanism of state-dependent sodium channel block by these compounds, and identify the molecular determinants of PTI binding to sodium channels. This research will provide new insight into the structure of the local anesthetic receptor and its role in the neurotoxic actions of PTIs.
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