Reciprocal Control of hERG Stability by Hsp70 and Hsc70 with Implication for Restoration of LQT2 Mutant Stability
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概要
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<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.
著者
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Kurata Yasutaka
Department Of Cardiovascular Medicine Faculty Of Medicine Tottori University
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YOSHIDA Akio
Department of Cardiovascular Medicine, Tottori University Faculty of Medicine
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Li Peili
Department Of Genetic Medicine And Regenerative Therapeutics Institute Of Regenerative Medicine And
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Miake Junichiro
Department Of Cardiovascular Medicine Tottori University School Of Medicine
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Shirayoshi Yasuaki
Department Of Genetic Medicine And Regenerative Therapeutics Institute Of Regenerative Medicine And
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Wu Jie
Department Of Applied Physics The University Of Tokyo
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Toyoda Futoshi
Department Of Physiology Shiga University Of Medical Science
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Yamamoto Yasutaka
Department Of Adaptive Machine Systems Osaka University
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Kato Masaru
Department Of Analytical Chemistry School Of Pharmaceutical Sciences University Of Shizuoka
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Matsuura Hiroshi
Department Of Applied Biological Chemistry Graduate School Of Agricultural And Life Sciences The Uni
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Hiraoka Masayasu
Department Of Cardilvascular Disease Medical Research Institute Tokyo Medical And Dental University
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Horie Minoru
Department Of Cardiac Physiology National Cardiovascular Center Research Institute
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Nakai Akira
Department Of Biochemistry And Molecular Biology Yamaguchi University Graduate School Of Medicine
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Igawa Osamu
Department Of Cardiovascular Medicine Faculty Of Medicine Tottori University
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Ninomiya Haruaki
Department Of Biological Regulation Faculty Of Medicine Tottori University
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Hisatome Ichiro
Department Of Cardiology Kitano Hospital Medical Research Institute
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Hiraoka Masayasu
Department of Cardiovascular Diseases, Tokyo Medical and Dental University
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Igawa Osamu
Department of Cardiovascular Medicine, Tottori University
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Ninomiya Haruaki
Department of Biological Regulation, Tottori University
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Higaki Katsumi
Research Center for Bioscience and Technology, Tottori University
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Yamamoto Yasutaka
Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
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Li Peili
Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
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Hisatome Ichiro
Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
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Shirayoshi Yasuaki
Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University
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Nakai Akira
Department of Applied Chemistry, Faculty of Engineering, Okayama University
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Nakai Akira
Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine
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