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The human ether-à -go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier K ϩ current (I Kr ) important for cardiac repolarization. Dysfunction of the hERG channel causes long QT syndrome (LQTS). Although diverse compounds reduce the hERG current (I hERG ) by blocking the channel, probucol, a cholesterol-lowering drug that causes LQTS, reduces I hERG by decreasing plasma-membrane hERG protein expression. Here, we investigated the mechanisms of probucol effects on hERG expression levels. Our data demonstrate that probucol accelerated the degradation of mature hERG channels, which associated with caveolin-1 (Cav1) in hERG-expressing HEK cells. In human embryonic kidney (HEK) cells without hERG expression, probucol promoted endogenous Cav1 degradation. In hERG-expressing HEK cells, overexpression of Cav1 enhanced, whereas knockdown of Cav1 impeded, probucol-induced reduction of mature hERG channels. Thus, probucol reduces hERG expression through accelerating Cav1 turnover. The effects of probucol on Cav1 and hERG result from probucol's cholesterol-disrupting action, because low-density lipoprotein (LDL), a potent cholesterol carrier, effectively prevented probucol-induced reduction of I hERG in hERG-expressing HEK cells and of I Kr in neonatal rat cardiomyocytes. Our data provide evidence that targeting hERG-interacting protein caveolin represents a novel mechanism for drugs to decrease hERG expression and cause LQTS.

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