Involvement of Caveolin in Low K+-induced Endocytic Degradation of Cell-surface Human Ether-a-go-go-related Gene (hERG) Channels

Reduction in the rapidly activating delayed rectifier K+ channel current (I-Kr) due to either mutations in the human ether-a-go-go-related gene (hERG) or drug block causes inherited or drug-induced long QT syndrome. A reduction in extracellular K+ concentration ([K+](o)) exacerbates long QT syndrome. Recently, we demonstrated that lowering [K+](o) promotes degradation of I-Kr in rabbit ventricular myocytes and of the hERG channel stably expressed in HEK 293 cells. In this study, we investigated the degradation pathways of hERG channels under low K+ conditions. We demonstrate that under low K+ conditions, mature hERG channels and caveolin-1 (Cav1) displayed a parallel time-dependent reduction. Mature hERG channels coprecipitated with Cav1 in co-immunoprecipitation analysis, and internalized hERG channels colocalized with Cav1 in immunocytochemistry analysis. Overexpression of Cav1 accelerated internalization of mature hERG channels in 0 mM K-o(+), whereas knockdown of Cav1 impeded this process. In addition, knockdown of dynamin 2 using siRNA transfection significantly impeded hERG internalization and degradation under low K-o(+) conditions. In cultured neonatal rat ventricular myocytes, knockdown of caveolin-3 significantly impeded low K-o(+)-induced reduction of IKr. Our data indicate that a caveolin-dependent endocytic route is involved in low K-o(+)-induced degradation of mature hERG channels.