An alanine in segment 3 of domain III (IIIS3) of the cockroach sodium channel contributes to the low pyrethrold sensitivity of an alternative splice variant

In a previous study, we showed that two alternative exons (G1 and G2 encoding IIIS3-S4) were involved in the differential sensitivity of two cockroach sodium channel splice variants, BgNa(v)1-1 and BgNa(v)2-1 (previously called KD1 and KD2), to deltamethrin, a pyrethroid insecticide (Tan, et al., 2002b. Alternative splicing of an insect sodium channel gene generates pharmacologically distinct sodium channels. J. Neurosci. 22, 5300-5309.). Here, we report the identification of an amino acid residue in exon G2 that contributes to the low deltamethrin sensitivity of BgNav2-1. Replacement of A 1356 in BgNa,2-1 with the corresponding V 1356 in BgNa, 1-1 enhanced the sensitivity of the BgNav2-1 channel to deltamethrin by six-fold. Conversely, substitution of V 13 56 with A 1356 in BgNa, 1-1 produced a recombinant BgNav 1-1 channel that was 5-fold more resistant to deltamethrin. These results demonstrate that A 1356 contributes to the low sensitivity of BgNav2-1 to deltamethrin. A1356V substitution also shifted the voltage-dependence of activation by 10 mV in the hyperpolarizing direction. Possible mechanisms by which this amino acid change affects the action of pyrethroids on the sodium channel are discussed.