POINT MUTATIONS IN THE DROSOPHILA SODIUM-CHANNEL GENE PARA ASSOCIATEDWITH RESISTANCE TO DDT AND PYRETHROID INSECTICIDES

The gene para in Drosophila melanogaster encodes an alpha subunit of v oltage-activated sodium channels, the presumed site of action of DDT a nd pyrethroid insecticides. We used an existing collection of Drosophi la para mutants to examine the molecular basis of target-site resistan ce to pyrethroids and DDT, Six out of thirteen mutants tested were ass ociated with a largely dominant. 10- to 30-fold increase in DDT resist ance. The amino acid lesions associated with these alleles defined fou r sites in the sodium channel polypeptide where a mutational change ca n cause resistance: within the intracellular loop between S4 and S5 in homology domains I and III, within the pore region of homology domain III, and within SG in homology domain III. Some of these sites are an alogous with those defined by knockdown resistance (kdr) and super-kdr resistance-associated mutations in houseflies and other insects, but are located in different homologous units of the channel polypeptide. We find a striking synergism in resistance levels with particular hete rozygous combinations of para alleles that appears to mimic the super- kdr double mutant housefly phenotype. Our results indicate that the al leles analyzed from natural populations represent only a subset of mut ations that can confer resistance. The implications for the binding si te of pyrethroids and mechanisms of target-site insensitivity are disc ussed.