Functional reconstitution of rat Na_v1.6 sodium channels in vitro for studies of pyrethroid action

The ability to reconstitute sodium channel function and pharmacology in vitro using cloned subunits of known structure has greatly enhanced our understanding of the action of pyrethroid insecticides at this target and the structural determinants of resistance and interspecies selectivity. However, the use of reconstituted channels raises three critical questions: (1) Which subunits and subunit combinations should be used? (2) Which heterologous expression system is preferred? (3) Which combination of subunits and expression system best represents the function of native neuronal channels in the organism of interest? This review considers these questions from the perspective of recent research in this laboratory on the action of pyrethroid insecticides on rat Na_v1.6 sodium channels by comparing the effects of heteroligomeric complex composition on channel function and insecticide response when channels are expressed in either Xenopus oocytes or stably-transformed HEK293 cells. These comparisons provide new insight into the influence of cellular context on the functional and pharmacological properties of expressed channels, the modulatory effects of sodium channel auxiliary subunits on the action of pyrethroids, and the relative fidelity of the Xenopus oocyte and HEK293 cell expression systems as model systems for studying of channel function and pyrethroid action.