Three mutations identified in the voltage-sensitive sodium channel α-subunit gene of permethrin-resistant human head lice reduce the permethrin sensitivity of house fly Vssc1 sodium channels expressed in Xenopus oocytes

Point mutations in the para-orthologous sodium channel a-subunit of the head louse (M8151, T9171, and L920F) are associated with permethrin resistance and DDT resistance. These mutations were inserted in all combinations using site-directed mutagenesis at the corresponding amino acid sequence positions (M8271, T9291, and L932F) of the house fly para-orthologous voltage-sensitive sodium channel a-subunit (Vssc1(WT)) gene and heterologously co-expressed with the sodium channel auxiliary subunit of house fly (Vssc beta) in Xenopus oocytes. The double mutant possessing M8271 and T9291 (Vssc1(MITI)/Vssc beta) caused a similar to 4.0 mV hyperpolarizing shift and the triple mutant, Vssc1(MITILF)/Vssc beta, caused a similar to 3.2 mV depolarizing shift in the voltage dependence of activation curves. Vssc1(MITI)/VSSC beta, Vssc1(TILF)/Vssc beta, and Vssc1(MITILF)/Vssc beta caused depolarizing shifts (similar to 6.6, similar to 7.6, and similar to 8.8 mV, respectively) in the voltage dependence of steady-state inactivation curves. The M8271 and L932F mutations reduced permethrin sensitivity when expressed alone but the T9291 mutation, either alone or in combination, virtually abolished permethrin sensitivity. Thus, the T9291 mutation is the principal cause of permethrin resistance in head lice. Comparison of the expression rates of channels containing single, double and triple mutations with that of Vssc1(WT)/Vssc beta channels indicates that the M827I mutation may play a role in rescuing the decreased expression of channels containing T9291. (C) 2007 Elsevier Ltd. All rights reserved.