Pyrethroid insecticides are widely used as one of the most effective control measures in the global fight against agricultural arthropod pests and
mosquito-borne diseases, including
malaria and
dengue. They exert toxic effects by altering the function of
voltage-gated sodium channels, which are essential for proper electrical signaling in the nervous system. A major threat to the sustained use of
pyrethroids for vector control is the emergence of mosquito resistance to
pyrethroids worldwide. Here, we report the successful expression of a
sodium channel, AaNav1-1, from Aedes aegypti in Xenopus oocytes, and the functional examination of nine
sodium channel mutations that are associated with
pyrethroid resistance in various Ae. aegypti and Anopheles gambiae populations around the world. Our analysis shows that five of the nine mutations reduce AaNav1-1 sensitivity to
pyrethroids. Computer modeling and further mutational analysis revealed a surprising finding: Although two of the five confirmed mutations map to a previously proposed
pyrethroid-receptor site in the house fly
sodium channel, the other three mutations are mapped to a second receptor site. Discovery of this second putative receptor site provides a dual-receptor paradigm that could explain much of the molecular mechanisms of
pyrethroid action and resistance as well as the high selectivity of
pyrethroids on insect vs. mammalian
sodium channels. Results from this study could impact future prediction and monitoring of
pyrethroid resistance in mosquitoes and other arthropod pests and disease vectors.