Abstract
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 calcium channels. Therefore, the present study compared the ability of 11 structurally diverse pyrethroids to evoke Ca2+ influx in primary cultures of mouse neocortical neurons. Nine pyrethroids (tefluthrin, deltamethrin, λ-cyhalothrin, β-cyfluthrin, esfenvalerate, S-bioallethrin, fenpropathrin, cypermethrin, and bifenthrin) produced concentration-dependent elevations in intracellular calcium concentration ([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 all were within one order of magnitude. Tetrodotoxin blocked increases in [Ca2+]i caused by all nine active pyrethroids, indicating that the effects depended on VGSC activation. The pathways for deltamethrin- and tefluthrin-induced Ca2+ influx include N-methyl-d-aspartic acid receptors, L-type Ca2+ channels, and reverse mode of operation of the 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.
Footnotes
This work was supported by the U.S. Environmental Protection Agency [Grant PR-RT-08-00545] (to T.F.M.), and the National Institutes of Health National Center for Research Resources [Grant G20RR024001].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.171850.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- VGSC
- voltage-gated sodium channel
- BDNF
- brain-derived neurotropic factor
- NMDA
- N-methyl-d-aspartic acid
- TTX
- tetrodotoxin
- VGCC
- voltage-gated calcium channel
- [Ca2+]i
- intracellular calcium concentration
- DIV
- days in vitro
- ANOVA
- analysis of variance
- HEK
- human embryonic kidney
- DMSO
- dimethyl sulfoxide
- IP3
- inositol(1,4,5)triphosphate
- PLC
- phospholipase C
- CI
- confidence interval
- AUC
- area under the curve
- MK-801
- (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
- 2-APB
- 2-aminoethoxydiphenylborane
- KBR-7943
- 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate
- U73122
- 1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione.
- Received June 23, 2010.
- Accepted September 24, 2010.
- U.S. Government work not protected by U.S. copyright
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