Involvement of caveolin in probucol-induced reduction in hERG plasma-membrane expression

Jun Guo, Xian Li, Heidi Shallow, Jianmin Xu, Tonghua Yang, Hamid Massaeli, Wentao Li, Tao Sun, Grant N. Pierce, Shetuan Zhang

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Abstract

The human ether-á-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, reducesIhERG 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. Cipyright

Original languageEnglish
Pages (from-to)806-813
Number of pages8
JournalMolecular Pharmacology
Volume79
Issue number5
DOIs
Publication statusPublished - 1 May 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Guo, J., Li, X., Shallow, H., Xu, J., Yang, T., Massaeli, H., Li, W., Sun, T., Pierce, G. N., & Zhang, S. (2011). Involvement of caveolin in probucol-induced reduction in hERG plasma-membrane expression. Molecular Pharmacology, 79(5), 806-813. https://doi.org/10.1124/mol.110.069419