Mutations in DIIS5 and the DIIS4–S5 linker of Drosophila melanogaster sodium channel define binding domains for pyrethroids and DDT

• Published in: FEBS letters 2007-11, Vol.581 (28), p.5485-5492
• Main Authors: Usherwood, P.N.R., Davies, T.G.E., Mellor, I.R., O’Reilly, A.O., Peng, F., Vais, H., Khambay, B.P.S., Field, L.M., Williamson, M.S.
• Format: Article
• Language: English
• Subjects: Animals; Computer modelling; DDT; DDT - chemistry; DDT - pharmacology; Drosophila; Drosophila melanogaster; Drosophila melanogaster - drug effects; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Electrophysiology; IIS4–S5 linker; IIS5 helix; inactivation onset time constant; integral modification; M I; Models, Molecular; Molecular Sequence Data; Molecular Structure; Mutation - genetics; Patch-Clamp Techniques; percentage channel modification; Protein Binding; Pyrethrins - chemistry; Pyrethrins - pharmacology; Pyrethroid; Sequence Alignment; Sodium channel; Sodium Channels - chemistry; Sodium Channels - genetics; Sodium Channels - metabolism; tail current decay time constant; the voltage for half-maximal current activation; time constant for recovery from inactivation; V 0.5 activation; Xenopus laevis; τ decay; τ onset; τ recovery
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2007.10.057

Mutations in the DIIS4–S5 linker and DIIS5 have identified hotspots of pyrethroid and DDT interaction with the Drosophila para sodium channel. Wild-type and mutant channels were expressed in Xenopus oocytes and subjected to voltage-clamp analysis. Substitutions L914I, M918T, L925I, T929I and C933A decreased deltamethrin potency, M918T, L925I and T929I decreased permethrin potency and T929I, L925I and I936V decreased fenfluthrin potency. DDT potency was unaffected by M918T, but abolished by T929I and reduced by L925I, L932F and I936V, suggesting that DIIS5 contains at least part of the DDT binding domain. The data support a computer model of pyrethroid and DDT binding.