Involvement of Caveolin-1 in Probucol-Reduced hERG Membrane Expression

Abstract

The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier K+ current (IKr) important for cardiac repolarization. Dysfunction of hERG channels causes Long QT Syndrome (LQTS). While diverse compounds reduce the hERG current (IhERG) by blocking hERG channels, probucol, a cholesterol-lowering drug that causes LQTS, reduces IhERG by decreasing hERG channel expression in the plasma membrane. In the present study, we investigated the mechanisms of probucol effects on hERG expression. Probucol did not block hERG forward trafficking; it instead accelerated degradation of mature hERG channels. Immunocytochemistry and co-immunoprecipitation (Co-IP) data demonstrated association between hERG channels and caveolin-1 (Cav-1). In HEK cells without hERG expression, probucol promoted endogenous Cav-1 degradation. In hERG-expressing HEK cells, overexpression of Cav-1 enhanced, whereas knockdown of Cav-1 impeded probucol-induced reduction of hERG channels. Thus, probucol reduces hERG expression through accelerating Cav-1 turnover. The effects of probucol on Cav-1 and hERG result from probucol's cholesterol-disrupting action, since low density lipoprotein (LDL), a potent cholesterol carrier, effectively prevented probucol-induced reduction of IhERG in hERG-HEK cells and of IKr in cultured neonatal rat ventricular myocytes. In conclusion, our data provide evidence that targeting hERG-interacting protein, caveolin, represents a novel mechanism for drug-induced hERG reduction and LQTS. (Supported by the Canadian Institutes of Health Research)