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Mechanisms of pyrethroid insecticide-induced stimulation of calcium influx in neocortical neurons
Citation:
Cao, Z., TIM SHAFER, AND T. F. Murray. Mechanisms of pyrethroid insecticide-induced stimulation of calcium influx in neocortical neurons. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 336(1):197-205, (2011).
Impact/Purpose:
There have been numerous reports in the literature that pyrethroids may directly activate calcium entry through voltage-gated calcium channels, and that this action may be a key event in the mode of action of pyrethroids. However, most of these reports used broken cell preparations from the nervous system or non-neuronal and/or non-mammalian systems (e.g. Xenopus oocytes) to express mammalian voltage-gated calcium channels. These systems may not accurately reflect the actions of pyrethroids in intact mammalian neurons. The methods used in this paper allow pyrethroid actions on calcium channels to be studied in an intact mammalian neurons, and therefore may be more reflective ofthe actions of pyrethroids in vivo.
Description:
Pyrethroid insecticides bind to voltage-gated sodium channels (VGSCs) and modify their gating kinetics, thereby disrupting neuronal function. Pyrethroids have also been reported to alter the function of other channel types, including activation of voltage-gated Ca2+ calcium channels (VGCCs). Therefore, the present study compared the ability of eleven structurally diverse pyrethroids to evoke Ca2+ influx in primary cultures of mouse neocortical neurons. Nine pyrethroids including tefluthrin, deltamethrin, A-cyhalothrin, B-cyfluthrin, esfenvalerate, S-bioallethrin, fenpropathrin, cypermethrin and bifenthrin produced concentration-dependent elevations in [Ca2+]i in neocortical neurons. Permethrin and resmethrin were without effect on [Ca2+]i. These pyrethroids displayed a range of efficacies on Ca2+ influx; however, the EC50 values for active pyrethroids were all within one order of magnitude. Tetrodotoxin (TTX) blocked increases in [Ca2+]i caused by all nine active pyrethroids, indicating that the effects were dependent on VGSC activation. The pathways for deltamethrin-induced Ca2+ influx include NMDA receptors, L-type Ca2+ channels and reverse mode of operation ofthe Na+/Ca2+ exchanger inasmuch as antagonists of these sites blocked deltamethrin-induced Ca2+ influx. These data demonstrate that pyrethroids stimulate Ca2+ entry into neurons subsequent to their actions on VGSCs. This Ca2+ entry may underlie reports of pyrethroid-induced gene transcription. Footnote (a)This work was supported by the US Environmental Protect Agency [Grant PR-RT-0800545] (to T.F.M.), and Grant Number G20RR024001 from the National Center for Research Resources. The content is solely the responsibility ofthe authors and does not necessarily represent the official views ofthe National Center for Research Resources or the National Institutes ofHealth." (b)This document has been subjected to review by the National Health and Environmental Effects Research Laboratory and is approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
