Differential sensitivity of rat voltage-sensitive sodium channel isoforms to pyrazoline-type insecticides


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Abstract

Pyrazoline-type insecticides are potent inhibitors of insect and mammalian voltage-sensitive sodium channels. In mammals, there are nine sodium channel α subunit isoforms that have unique distributions and pharmacological properties, but no published data exist that compare the relative sensitivity of these different mammalian sodium channel isoforms to inhibition by pyrazoline-type insecticides. This study employed the Xenopus oocyte expression system to examine the relative sensitivity of rat Nav1.2a, Nav1.4, Nav1.5, and Nav1.8 sodium channel α subunit isoforms to the pyrazoline-type insecticides indoxacarb, DCJW, and RH 3421. Additionally, we assessed the effect of coexpression with the rat β1 auxiliary subunit on the sensitivity of the Nav1.2a and Nav1.4 isoforms to these compounds. The relative sensitivity of the four sodium channel α subunits differed for each of the three compounds we examined. With DCJW, the order of sensitivity was Nav1.4 > Nav1.2a > Nav1.5 > Nav1.8. In contrast, the relative sensitivity of these isoforms to indoxacarb differed from that to DCJW: the Nav1.8 isoform was most sensitive, the Nav1.4 isoform was completely insensitive, and the sensitivities of the Nav1.5 and Nav1.2a isoforms were intermediate between these two extremes. Moreover, the pattern of sensitivity to RH 3421 among these four isoforms was different from that for either indoxacarb or DCJW: the Nav1.4 isoform was most sensitive to RH 3421, whereas the sensitivities of the remaining three isoforms were substantially less than that of the Nav1.4 isoform and were approximately equivalent. The only statistically significant effect of coexpression of either the Nav1.2a or Nav1.4 isoforms with the β1 subunit was the modest reduction in the sensitivity of the Nav1.2a isoform to RH 3421. These results demonstrate that mammalian sodium channel isoforms differ in their sensitivities to pyrazoline-type insecticides.

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