The molecular interactions of pyrethroid insecticides with insect and mammalian sodium channels

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Abstract
Recent progress in the cloning of α (para) and β (TipE) Na channel sub‐units fromDrosophila melanogaster(fruit fly) andMusca domestica(housefly) have facilitated functional expression studies of insect Na channels inXenopus laevisoocytes, assayed by voltage clamp techniques. The effects of Type I and Type II pyrethroids on the biophysical properties of these channels are critically reviewed. Pyrethroid resistance mutations (termedkdrandsuper‐kdr) that reduce the sensitivity of the insect Na channel to pyrethroids have been identified in a range of insect species. Some of these mutations (eg L1014F, M918T and T929I) have been incorporated into theparaNa channel ofDrosophila, either individually or in combination, to investigate their effects on the sensitivity of this channel to pyrethroids. Thekdrmutation (L1014F) shifts the voltage dependence of both activation and steady‐state inactivation by ∼5 mV towards more positive potentials and facilitates Na channel inactivation. Incorporation of thesuper‐kdrmutation (M918T) into theDrosophilaNa channel also increases channel inactivation and causes a >100‐fold reduction in deltamethrin sensitivity. These effects are shared by T929I, an alternative mutation that conferssuper‐kdr‐like resistance. Parallel studies have been undertaken using the rat IIA Na channel to investigate the molecular basis for the low sensitivity of mammalian brain Na channels to pyrethroids. Rat IIA channels containing the mutation L1014F exhibit a shift in their mid‐point potential for Na activation, but their overall sensitivity to permethrin remains similar to that of the wild‐type rat channel (ie both are 1000‐fold less sensitive than the wild‐type insect channel). Mammalian neuronal Na channels have an isoleucine rather than a methionine at the position (874) corresponding to thesuper‐kdr(M918) residue of the insect channel. Replacement of the isoleucine of the wild‐type rat IIA Na channel with a methionine (I874M) increases deltamethrin sensitivity 100‐fold. In this way, studies of wild‐type and mutant Na channels of insects and mammals are providing a molecular understanding ofkdrandsuper‐kdrresistance in insects, and of the low pyrethroid sensitivity of most mammalian Na channels. They are also giving valuable insights into the binding sites for pyrethroids on these channels.© 2001 Society of Chemical Industry

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