INHIBITION OF A NEURONAL VOLTAGE-DEPENDENT CHLORIDE CHANNEL BY THE TYPE-II PYRETHROID, DELTAMETHRIN

Following the previous finding that the Type II pyrethroid, deltamethrin, increased membrane resistance in peripheral nerve and muscle in a chloride-dependent manner, the action of deltamethrin on neuronal voltage-dependent chloride channels was assessed using inside-out patches from NIE-115 neuroblastoma cells. These were bathed in symmetrical solutions, containing 149 mM chloride and the membrane potential stepped from 0 mV to voltages ranging from +/- 10 to 80 mV for 2 or 5 sec. Active patches contained large conductance channels (343 +/- 11 pS, n = 8), which inactivated relatively slowly during the voltage step and could be resolved into a number of substates. The channels were confirmed as being chloride specific on the basis of substitution experiments with isethionate and pharmacological blockade by 9-anthracene carboxylic acid (9-ACA). Within 20 min of adding deltamethrin (2 muM) to the bath solution, open channel probability (P(O)) fell from 0.50 +/- 0.06 to 0.24 +/- 0.04 (n = 11), a highly significant result. Glycerinformal solvent alone (0.1 % v/v) caused a non-significant rise to 0.65 +/- 0.09 (n = 4). The decreased open channel probability after deltamethrin was due to an increased incidence of both the closed channel state and low conductance substates- In addition, deltamethrin frequently caused flickering between substates similar to that seen after 9-ACA. Deltamethrin did not change single channel conductance, current-voltage relationship or time-dependent channel inactivation, but decreased open channel probability over the complete range of membrane voltage tested. This inhibition of voltage-dependent chloride channels by deltamethrin confirmed the earlier findings and indicated a novel site of action with important toxicological and therapeutic implications, which may also contribute to the differential pharmacology of Type I and Type II pyrethroids.