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

Abstract

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.

Widespread convergence in toxin resistance by predictable molecular evolution

“…Our data further emphasize how the application of similar, strong, selective pressures appear to underpin the convergent evolution of resistance to both naturally occurring (e.g., cardiac glycosides, tetrodotoxin, venom toxins) (7-9, 40) and anthropogenically applied (e.g., insecticides, pesticides) (10,30,31,41) toxic molecules. Interestingly, many of these toxic molecules appear to interfere with essential components involved in the transport of ions across cell membranes, typically by impinging upon ion channel or ion pump function (7-9, 30, 31, 40, 42).…”

“…Single point mutations in domain II of arthropod Na V channels (mostly commonly a semiconservative L1014F mutation in the pore-forming domain II S6 helix) reduce deltamethrin affinity by only 17-fold, but this is sufficient to confer a high level of resistance to this pyrethroid (30). Analogous to bufalin resistance, a higher level of (27).…”

Analogous pleiotropic effects of insecticide resistance genotypes in peach–potato aphids and houseflies

“…Such mutations almost certainly have the same function in aphids, houseflies, and in all other insects in which they occur (Vais et al, 2001). However, in addition to making the channel protein less sensitive to some insecticides, these mutations also alter the normal gating properties of the sodium channel.…”

“…In the same species, a point mutation of a voltagegated sodium channel gene confers cross-resistance to pyrethroids and DDT (knockdown resistance or kdr) (Martinez-Torres et al, 1999). This latter mutation is common to many pyrethroid-resistant insect species, including Musca domestica (Diptera: Muscidae) (Vais et al, 2001).…”

Nervous System and Gastrointestinal Effects of the Insecticide Esfenvalerate on the Rat: An <i>Ex Vivo</i> Study

“…Normally, these channels remain open only for about 1 ms, before being inactivated, then closed. Voltage-clamp studies have shown that pyrethroids slow down both activation and inactivation kinetics of the channels, leading to depolarizing after potentials [5]. If a sufficient fraction of channels is modified, the after potential reaches the cell's threshold for excitation and repetitive after discharges are produced which are in the background of the poisoning symptoms [6].…”