Mutations in the skeletal muscle ryanodine receptor (RyR1) cause malignant hyperthermia (MH) and central core disease (CCD), whereas mutations in the cardiac ryanodine receptor (RyR2) lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most disease-associated RyR1 and RyR2 mutations are located in the N-terminal, central, and C-terminal regions of the corresponding ryanodine receptor (RyR) isoform. An increasing body of evidence demonstrates that CPVT-associated RyR2 mutations enhance the propensity for spontaneous Ca2+ release during store Ca2+ overload, a process known as store overload-induced Ca2+ release (SOICR). Considering the similar locations of disease-associated RyR1 and RyR2 mutations in the RyR structure, we hypothesize that like CPVT-associated RyR2 mutations, MH/CCD-associated RyR1 mutations also enhance SOICR. To test this hypothesis, we determined the impact on SOICR of 12 MH/CCD-associated RyR1 mutations E2347-del, R2163H, G2434R, R2435L, R2435H, and R2454H located in the central region, and Y4796C, T4826I, L4838V, A4940T, G4943V, and P4973L located in the C-terminal region of the channel. We found that all these RyR1 mutations reduced the threshold for SOICR. Dantrolene, an acute treatment for MH, suppressed SOICR in HEK293 cells expressing the RyR1 mutants R164C, Y523S, R2136H, R2435H, and Y4796C. Interestingly, carvedilol, a commonly used β-blocker that suppresses RyR2-mediated SOICR, also inhibits SOICR in these RyR1 mutant HEK293 cells. Therefore, these results indicate that a reduced SOICR threshold is a common defect of MH/CCD-associated RyR1 mutations, and that carvedilol, like dantrolene, can suppress RyR1-mediated SOICR. Clinical studies of the effectiveness of carvedilol as a long-term treatment for MH/CCD or other RyR1-associated disorders may be warranted.
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August 2017
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The distribution of haemagglutinin (green) and β-catenin (red) in MDCK cells overexpressing Akt1-HA. In this issue of the Biochemical Journal, Castañeda et al. report on the suppression of Akt/β-catenin-mediated cell proliferation by the the inhibition of 14-3-3ζ expression (see pages 2679–2689).
Research Article|
August 07 2017
Reduced threshold for store overload-induced Ca2+ release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease
Wenqian Chen;
Wenqian Chen
*
1Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Andrea Koop;
Andrea Koop
1Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Yingjie Liu;
Yingjie Liu
*
1Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Wenting Guo;
Wenting Guo
*
1Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Jinhong Wei;
Jinhong Wei
†
1Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Ruiwu Wang;
Ruiwu Wang
1Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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David H. MacLennan;
David H. MacLennan
2Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada
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Robert T. Dirksen;
Robert T. Dirksen
3Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, U.S.A.
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Sui Rong Wayne Chen
Sui Rong Wayne Chen
‡
1Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
Correspondence: S.R. Wayne Chen (swchen@ucalgary.ca)
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Publisher: Portland Press Ltd
Received:
April 14 2017
Revision Received:
June 30 2017
Accepted:
July 06 2017
Accepted Manuscript online:
July 07 2017
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem J (2017) 474 (16): 2749–2761.
Article history
Received:
April 14 2017
Revision Received:
June 30 2017
Accepted:
July 06 2017
Accepted Manuscript online:
July 07 2017
Citation
Wenqian Chen, Andrea Koop, Yingjie Liu, Wenting Guo, Jinhong Wei, Ruiwu Wang, David H. MacLennan, Robert T. Dirksen, Sui Rong Wayne Chen; Reduced threshold for store overload-induced Ca2+ release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease. Biochem J 15 August 2017; 474 (16): 2749–2761. doi: https://doi.org/10.1042/BCJ20170282
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