Abstract
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.
Footnotes
This work was supported by the Canadian Institutes of Health Research [Grant MOP 84229] S.Z. is a recipient of the Canadian Institutes of Health Research New Investigator Award.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.069419.
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ABBREVIATIONS:
- hERG
- human ether-à-go-go-related gene
- BFA
- brefeldin A
- Cav1
- caveolin-1
- CHX
- cycloheximide
- IhERG
- human ether-a-go-go-related gene current
- LDL
- low-density lipoprotein
- LQTS
- long QT syndrome
- siRNA
- small interfering RNA
- HPLC
- high-performance liquid chromatography
- Cav3
- caveolin-3
- CoIP
- coimmunoprecipitation
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase.
- Received October 13, 2010.
- Accepted January 28, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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