Knockout of DSC1 antagonizes kdr-like resistance in Drosophila melanogaster

Pyrethroid insecticides prolong the opening of voltage-gated sodium channels resulting in the hyperexcitability of the nervous system. Mutations in sodium channels result in knockdown-resistance (kdr) to pyrethroids in many arthropod pests and disease vectors. Similarly, in the model insect Drosophila melanogaster, kdr-like mutations in temperature-sensitive paralytic mutants (para^ts) have been implicated in pyrethroid resistance. However, knockout of another sodium channel-like gene, DSC1, increased susceptibility to pyrethroids in D. melanogaster by enhancing the sensitivity of the nervous system to pyrethroids. In this study, we investigate the molecular mechanism of kdr-like resistance in D. melanogaster, and examine the effect of DSC1 knockout on pyrethroid resistance. Previously, an I265N sodium channel mutation was identified in the para^ts1 line that confers resistance to pyrethroids and DDT. Here we confirmed in the Xenopus oocyte expression system that the I265N mutation indeed reduced the sensitivity of a Drosophila sodium channel to permethrin and deltamethrin. Intriguingly, this kdr-like mutation is located closely to a recently uncovered pyrethroid receptor site 2 and likely confers resistance by reducing pyrethroid binding. We then generated a double mutation line by introducing the para^ts1 allele into a DSC1 knockout line.  We found the double mutation reduced both the I265N-mediated resistance and the DSC1KO-induced hypersensitivity. Our findings indicate the DSC1 knockout antagonized the kdr-like resistance in para^ts1, and implicate the potential of DSC1 channel blockers or modifiers in the management of pyrethroid resistance.