RT Journal Article SR Electronic T1 Involvement of Caveolin in Probucol-Induced Reduction in hERG Plasma-Membrane Expression JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 806 OP 813 DO 10.1124/mol.110.069419 VO 79 IS 5 A1 Jun Guo A1 Xian Li A1 Heidi Shallow A1 Jianmin Xu A1 Tonghua Yang A1 Hamid Massaeli A1 Wentao Li A1 Tao Sun A1 Grant N. Pierce A1 Shetuan Zhang YR 2011 UL http://molpharm.aspetjournals.org/content/79/5/806.abstract AB The human ether-à-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 the hERG channel causes long QT syndrome (LQTS). Although diverse compounds reduce the hERG current (IhERG) by blocking the channel, probucol, a cholesterol-lowering drug that causes LQTS, reduces IhERG 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 IhERG in hERG-expressing HEK cells and of IKr 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.