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NEUROPHARMACOLOGY
Biotechnology Laboratory, University of British Columbia, Vancouver, British Columbia, Canada (M.E.H., J.E.M., T.P.S.); and University-College of the Fraser Valley, Abbotsford, British Columbia, Canada (A.S.)
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 
1G (Cav3.1), 6.8 µM for L-type 1C (Cav1.2), and 6.7 µM for P/Q-type 1A (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 1G 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.
Address correspondence to: Dr. Anthony Stea, Department of Biology, University-College of the Fraser Valley, 33844 King Road, Abbotsford, British Columbia, Canada, V2S 7M8. E-mail: steat{at}ucfv.bc.ca
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