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  • Title: Mutations of the para sodium channel of Drosophila melanogaster identify putative binding sites for pyrethroids.
    Author: Vais H, Atkinson S, Pluteanu F, Goodson SJ, Devonshire AL, Williamson MS, Usherwood PN.
    Journal: Mol Pharmacol; 2003 Oct; 64(4):914-22. PubMed ID: 14500748.
    Abstract:
    The effects of two pyrethroids on recombinant wild-type and mutant (pyrethroid-resistant) Na+ channels of Drosophila melanogaster have been studied. Three mutations that confer resistance (kdr/superkdr) to pyrethroids were inserted, either individually or in combination, into the para Na+ channel of D. melanogaster: L1014F in domain IIS6, M918T in the IIS4-S5 linker, and T929I in domain IIS5. Channels were expressed in Xenopus laevis oocytes and the effects of the pyrethroids permethrin (type I) and deltamethrin (type II) on Na+ currents were investigated using voltage clamp. The Na+ channels deactivated slowly after deltamethrin treatment, the resultant "tail" currents being used to quantify the effects of this pyrethroid. The Hill slope of 2 for deltamethrin action on the wild-type channel and the mutant L1014F channel is indicative of cooperative binding at two or more sites on these channels. In contrast, binding to the mutants M918T and T929I is noncooperative. Tail currents for the wild-type channel and L1014F channel decayed biphasically, whereas those for M918T and T929I mutants decayed monophasically. The L1014F mutant was approximately 20-fold less sensitive than the wild-type to deltamethrin. Surprisingly, the sensitivity of the double mutant M918T+L1014F to deltamethrin was similar to that of M918T alone, whereas the sensitivity of T929I+L1014F was >30,000-fold lower than that of T929I. Permethrin was less potent than deltamethrin, and its binding to all channel types was noncooperative. The decays of permethrin-induced tail currents were exclusively monophasic. These findings are discussed in terms of the properties and possible locations of pyrethroid binding sites on the D. melanogaster Na+ channel.
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