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Research ArticleNEUROPHARMACOLOGY

Mammalian Voltage-Gated Calcium Channels Are Potently Blocked by the Pyrethroid Insecticide Allethrin

Michael E. Hildebrand, John E. McRory, Terrance P. Snutch and Anthony Stea
Journal of Pharmacology and Experimental Therapeutics March 2004, 308 (3) 805-813; DOI: https://doi.org/10.1124/jpet.103.058792
Michael E. Hildebrand
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John E. McRory
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Terrance P. Snutch
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Anthony Stea
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Abstract

Pyrethroids are commonly used insecticides for both household and agricultural applications. It is generally reported that voltage-gated sodium channels are the primary target for toxicity of these chemicals to humans. The phylogenetic and structural relatedness between sodium channels and voltagegated calcium (Ca) channels prompted us to examine the effects of the type 1 pyrethroid allethrin on the three major classes of mammalian calcium channels exogenously expressed in human embryonic kidney 293 cells. We report that all classes of mammalian calcium channels are targets for allethrin at concentrations very similar to those reported for interaction with sodium channels. Allethrin caused blockade with IC50 values of 7.0 μM for T-type α1G (Cav3.1), 6.8 μM for L-type α1C (Cav1.2), and 6.7 μM for P/Q-type α1A (Cav2.1) channels. Mechanistically, the blockade of calcium channels was found to be significantly different than the prolonged opening of mammalian sodium channels caused by pyrethroids. In all calcium channel subtypes tested, allethrin caused a significant acceleration of the inactivation kinetics and a hyperpolarizing shift in the voltage dependence of inactivation. The high-voltage-activated P/Q- and L-type channels showed a frequency of stimulation-dependent increase in block by allethrin, whereas the low-voltage-activated α1G subtype did not. Allethrin did not significantly modify the deactivation kinetics or current-voltage relationships of any of the calcium channel types. Our study indicates that calcium channels are another primary target for allethrin and suggests that blockade of different types of calcium channels may underlie some of the chronic effects of low-level pyrethroid poisoning.

Footnotes

  • ABBREVIATION: HEK, human embryonic kidney.

  • This work was supported by a grant from the Canadian Institute for Health Research (CIHR) and a CIHR Senior Scientist Award (to T.P.S.), fellowship support from the Natural Sciences and Engineering Research Council of Canada and the Michael Smith Foundation for Health Research (to M.E.H.), and research funding from the University-College of the Fraser Valley (to A.S.).

  • DOI: 10.1124/jpet.103.058792.

  • ↵1 Present address: Department of Physiology and Biophysics, Cellular and Molecular Neurobiology Research Group, University of Calgary, Calgary, Alberta, Canada.

    • Received August 18, 2003.
    • Accepted November 14, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 3
1 Mar 2004
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Research ArticleNEUROPHARMACOLOGY

Mammalian Voltage-Gated Calcium Channels Are Potently Blocked by the Pyrethroid Insecticide Allethrin

Michael E. Hildebrand, John E. McRory, Terrance P. Snutch and Anthony Stea
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 805-813; DOI: https://doi.org/10.1124/jpet.103.058792

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Research ArticleNEUROPHARMACOLOGY

Mammalian Voltage-Gated Calcium Channels Are Potently Blocked by the Pyrethroid Insecticide Allethrin

Michael E. Hildebrand, John E. McRory, Terrance P. Snutch and Anthony Stea
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 805-813; DOI: https://doi.org/10.1124/jpet.103.058792
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