Reciprocal Control of hERG Stability by Hsp70 and Hsc70 with Implication for Restoration of LQT2 Mutant Stability

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Author(s)

    • Li Peili
    • Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
    • Wu Jie
    • Department of Cardiovascular Medicine, Shiga University of Medical Science
    • Horie Minoru
    • Department of Cardiovascular Medicine, Shiga University of Medical Science
    • Yoshida Akio
    • Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
    • Shirayoshi Yasuaki
    • Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
    • Hiraoka Masayasu
    • Department of Cardiovascular Diseases, Tokyo Medical and Dental University
    • Hisatome Ichiro
    • Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
    • Kato Masaru
    • Department of Cardiovascular Medicine, Tottori University
    • Yamamoto Yasutaka
    • Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
    • Igawa Osamu
    • Department of Cardiovascular Medicine, Tottori University
    • Nakai Akira
    • Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine
    • Higaki Katsumi
    • Research Center for Bioscience and Technology, Tottori University

Abstract

<B>Rationale:</B> The human ether-a-go-go-related gene (hERG) encodes the α subunit of the potassium current IKr. It is highly expressed in cardiomyocytes and its mutations cause long QT syndrome type 2. Heat shock protein (Hsp) 70 is known to promote maturation of hERG. Hsp70 and heat shock cognate (Hsc70) 70 has been suggested to play a similar function. However, Hsc70 has recently been reported to counteract Hsp70.<BR><B>Objective:</B> We investigated whether Hsc70 counteracts Hsp70 in the control of wild-type and mutant hERG stability.<BR><B>Methods and Results:</B> Coexpression of Hsp70 with hERG in HEK293 cells suppressed hERG ubiquitination and increased the levels of both immature and mature forms of hERG. Immunocytochemistry revealed increased levels of hERG in the endoplasmic reticulum and on the cell surface. Electrophysiological studies showed increased IKr. All these effects of Hsp70 were abolished by Hsc70 coexpression. Heat shock treatment of HL-1 mouse cardiomyocytes induced endogenous Hsp70, switched mouse ERG associated with Hsc70 to Hsp70, increased IKr, and shortened action potential duration. Channels with disease-causing missense mutations in intracellular domains had a higher binding capacity to Hsc70 than wild-type channels and channels with mutations in the pore region. Knockdown of Hsc70 by small interfering RNA or heat shock prevented degradation of mutant hERG proteins with mutations in intracellular domains.<BR><B>Conclusions:</B> These results indicate reciprocal control of hERG stability by Hsp70 and Hsc70. Hsc70 is a potential target in the treatment of LQT2 resulting from missense hERG mutations.

Journal

  • Journal of Arrhythmia

    Journal of Arrhythmia 27(Supplement), JAAC_2, 2011

    Japanese Heart Rhythm Society

Codes

  • NII Article ID (NAID)
    130002130408
  • Text Lang
    ENG
  • ISSN
    1880-4276
  • Data Source
    J-STAGE 
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