The molecular interactions of pyrethroid insecticides with insect and mammalian sodium channels.
Recent progress in the cloning of alpha (para) and beta (TipE) Na channel sub-units from Drosophila melanogaster (fruit fly) and Musca domestica (housefly) have facilitated functional expression studies of insect Na channels in Xenopus laevis oocytes, assayed by voltage clamp techniques. The effects of Type I and Type III pyrethroids on the biophysical properties of these channels are critically reviewed. Pyrethroid resistance mutations (termed kdr and super-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 (e.g. L1014F, M918T and T929I) have been incorporated into the para Na channel of Drosophila, either individually or in combination, to investigate their effects on the sensitivity of this channel to pyrethroids. The kdr mutation (L1014F) shifts the voltage dependence of both activation and steady-state inactivation by approximately 5 mV towards more positive potentials and facilitates Na channel inactivation. Incorporation of the super-kdr mutation (M918T) into the Drosophila Na channel also increases channel inactivation and causes a > 100-fold reduction in deltamethrin sensitivity. These effects are shared by T929I, an alternative mutation that confers super-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 (i.e. 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 the super-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 of kdr and super-kdr resistance 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.
Vais
H
H
Division of Molecular Toxicology, School of Life and Environmental Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
Williamson
M S
MS
Devonshire
A L
AL
Usherwood
P N
PN
D000818:Animals; D001921:Brain / Q000187:drug effects; D004331:Drosophila melanogaster / Q000187:drug effects*; D005260:Female; D006793:Houseflies / Q000187:drug effects*; D007305:Insecticide Resistance; D007306:Insecticides / Q000633:toxicity*; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation; D009474:Neurons / Q000187:drug effects; D011722:Pyrethrins / Q000633:toxicity*; D051381:Rats; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
D007306:Insecticides; D011722:Pyrethrins; D015222:Sodium Channels