Pyrethroid action on calcium channels: neurotoxicological implications
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- Clark, J.M. & Symington, S.B. Invert Neurosci (2007) 7: 3. doi:10.1007/s10158-006-0038-7
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Actions of cismethrin versus deltamethrin were compared using two functional attributes of rat brain synaptosomes. Both pyrethroids increased calcium influx but only deltamethrin increased Ca2+-dependent neurotransmitter release following K+-stimulated depolarization. The action of deltamethrin was stereospecific, concentration-dependent, and blocked by ω-conotoxin GVIA. These findings delineate a separate action for deltamethrin and implicate N-type rat brain Cav2.2 voltage-sensitive calcium channels (VSCC) as target sites that are consistent with the in vivo release of neurotransmitter caused by deltamethrin. Deltamethrin (10−7 M) reduced the peak current (approx. −47%) of heterologously expressed wild type Cav2.2 in a stereospecific manner. Mutation of threonine 422 to glutamic acid (T422E) in the α1-subunit results in a channel that functions as if it were permanently phosphorylated. Deltamethrin now increased peak current (approx. +49%) of T422E Cav2.2 in a stereospecific manner. Collectively, these results substantiate that Cav2.2 is directly modified by deltamethrin but the resulting perturbation is dependent upon the phosphorylation state of Cav2.2. Our findings may provide a partial explanation for the different toxic syndromes produced by these structurally-distinct pyrethroids.