Pyrethroid insecticides possess high insecticidal activities and low mammalian toxicity and represent one of the most powerful weapons in the global fight against malaria and other arthropod-borne human diseases. However, the efficacy of pyrethroids decreases due to emerging pyrethroid resistance. One major resistance mechanism, known as knockdown resistance (kdr), is caused by mutations in the voltage-gated sodium channel, the primary target of pyrethroids.  Recently, a new sodium channel mutation N1575Y in the linker connecting domains III and IV was found to co-exist with the L1014F kdr mutation in the transmembrane segment 6 of domain II (IIS6) in the African malaria vector Anopheles gambiae, and may confer a higher level of pyrethroid resistance. To examine the role of this new mutation in pyrethroid resistance, we introduced it into an Aedes aegypti sodium channel, AaNav1-1, alone or in combination with the L1014F mutation. Our functional analyses in Xenopus oocytes show that the N1575Y mutation per se did not alter AaNav1-1 sensitivity to pyrethroids permethrin and deltamethrin. However, the L1014F/N1575Y double mutant was 10-fold and 4-fold more resistant to permethrin and deltamethrin, respectively, than the L1014F channel. Furthermore, the N1575Y mutation also synergized the effect of L1014S, but not that of V1016G (both are in IIS6, but contribute to two distinct pyrethroid receptor sites). Computer modeling suggests that N1575Y could allosterically deform Site 2 (where L1014F/S are located) via a small shift of IIS6. Our study provides a molecular explanation for the synergism between N1575Y and L1014F/S on pyrethroid-resistance.

Mutation in the linker connecting domains III and IV of the <i>Anopheles gambiae</i> sodium channel synergizes the effect of mutations in the transmembrane segment 6 of domain II on pyrethroid resistance

248th National Meeting (2014)

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Mutation in the linker connecting domains III and IV of the Anopheles gambiae sodium channel synergizes the effect of mutations in the transmembrane segment 6 of domain II on pyrethroid resistance