Coexpression with auxiliary β subunits modulates the action of tefluthrin on rat Na v1.6 and Na v1.3 sodium channels

Abstract

We expressed the rat Na v1.3 and Na v1.6 sodium channel α subunit isoforms in Xenopus oocytes either alone or with the rat β1 and β2 auxiliary subunits in various combinations and assessed the sensitivity of the expressed channels to resting and use-dependent modification by the pyrethroid insecticide tefluthrin using the two-electrode voltage clamp technique. Coexpression with the β1 and β2 subunits, either individually or in combination, did not affecting the resting sensitivity of Na v1.6 channels to tefluthrin. Modification by tefluthrin of Na v1.6 channels in the absence of β subunits was not altered by the application of trains of high-frequency depolarizing prepulses. By contrast, coexpression of the Na v1.6 channel with the β1 subunit enhanced the extent of channel modification 2-fold following repeated depolarization. Coexpression of Na v1.6 with the β2 subunit also slightly enhanced modification following repeated depolarization, but coexpression of Na v1.6 with both β subunits caused enhanced modification following repeated depolarization that was indistinguishable from that found with Na v1.6 + β1 channels. In contrast to Na v1.6, the resting modification by tefluthrin of Na v1.3 channels expressed in the absence of β subunits was reduced by repeated depolarization. However, tefluthrin modification of the Na v1.3 α subunit expressed with both β subunits was enhanced 1.7-fold by repeated depolarization, thereby confirming that β subunit modulation of use-dependent effects was not confined to the Na v1.6 isoform. These results show that the actions of pyrethroids on mammalian sodium channels in the Xenopus oocyte expression system are determined in part by the interactions of the sodium channel α subunit with the auxiliary β subunits that are part of the heteromultimeric sodium channel complexes found in neurons and other excitable cells.