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 mol.110.069419
DO 10.1124/mol.110.069419
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/early/2011/01/28/mol.110.069419.abstract
AB The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier K+ channel (IKr) important for cardiac repolarization. Dysfunction of the hERG channel causes Long QT Syndrome (LQTS). While 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 demonstrated that probucol accelerated degradation of mature hERG channels which associated with caveolin-1 (Cav1) in hERG-expressing HEK cells. In 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, since 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.