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Molecular Pharmacology

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Research ArticleArticle

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 and Shetuan Zhang
Molecular Pharmacology May 2011, 79 (5) 806-813; DOI: https://doi.org/10.1124/mol.110.069419
Jun Guo
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Xian Li
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Heidi Shallow
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Jianmin Xu
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Tonghua Yang
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Hamid Massaeli
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Wentao Li
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Tao Sun
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Grant N. Pierce
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Shetuan Zhang
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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.

  • 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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Molecular Pharmacology: 79 (5)
Molecular Pharmacology
Vol. 79, Issue 5
1 May 2011
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Research ArticleArticle

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 and Shetuan Zhang
Molecular Pharmacology May 1, 2011, 79 (5) 806-813; DOI: https://doi.org/10.1124/mol.110.069419

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Research ArticleArticle

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 and Shetuan Zhang
Molecular Pharmacology May 1, 2011, 79 (5) 806-813; DOI: https://doi.org/10.1124/mol.110.069419
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