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Molecular Pharmacology

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Research ArticleArticle

Essential Role of Calmodulin in RyR Inhibition by Dantrolene

Ye Win Oo, Nieves Gomez-Hurtado, Kafa Walweel, Dirk F. van Helden, Mohammad S. Imtiaz, Bjorn C. Knollmann and Derek R. Laver
Molecular Pharmacology July 2015, 88 (1) 57-63; DOI: https://doi.org/10.1124/mol.115.097691
Ye Win Oo
School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (Y.W.O., K.W., D.F.H., M.S.I., D.R.L.); and Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee (N.G.-H., B.C.K.)
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Nieves Gomez-Hurtado
School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (Y.W.O., K.W., D.F.H., M.S.I., D.R.L.); and Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee (N.G.-H., B.C.K.)
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Kafa Walweel
School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (Y.W.O., K.W., D.F.H., M.S.I., D.R.L.); and Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee (N.G.-H., B.C.K.)
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Dirk F. van Helden
School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (Y.W.O., K.W., D.F.H., M.S.I., D.R.L.); and Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee (N.G.-H., B.C.K.)
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Mohammad S. Imtiaz
School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (Y.W.O., K.W., D.F.H., M.S.I., D.R.L.); and Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee (N.G.-H., B.C.K.)
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Bjorn C. Knollmann
School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (Y.W.O., K.W., D.F.H., M.S.I., D.R.L.); and Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee (N.G.-H., B.C.K.)
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Derek R. Laver
School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (Y.W.O., K.W., D.F.H., M.S.I., D.R.L.); and Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee (N.G.-H., B.C.K.)
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Abstract

Dantrolene is the first line therapy of malignant hyperthermia. Animal studies suggest that dantrolene also protects against heart failure and arrhythmias caused by spontaneous Ca2+ release. Although dantrolene inhibits Ca2+ release from the sarcoplasmic reticulum of skeletal and cardiac muscle preparations, its mechanism of action has remained controversial, because dantrolene does not inhibit single ryanodine receptor (RyR) Ca2+ release channels in lipid bilayers. Here we test the hypothesis that calmodulin (CaM), a physiologic RyR binding partner that is lost during incorporation into lipid bilayers, is required for dantrolene inhibition of RyR channels. In single channel recordings (100 nM cytoplasmic [Ca2+] + 2 mM ATP), dantrolene caused inhibition of RyR1 (rabbit skeletal muscle) and RyR2 (sheep) with a maximal inhibition of Po (Emax) to 52 ± 4% of control only after adding physiologic [CaM] = 100 nM. Dantrolene inhibited RyR2 with an IC50 of 0.16 ± 0.03 µM. Mutant N98S-CaM facilitated dantrolene inhibition with an IC50 = 5.9 ± 0.3 nM. In mouse cardiomyocytes, dantrolene had no effect on cardiac Ca2+ release in the absence of CaM, but reduced Ca2+ wave frequency (IC50 = 0.42 ± 0.18 µM, Emax = 47 ± 4%) and amplitude (IC50 = 0.19 ± 0.04 µM, Emax = 66 ± 4%) in the presence of 100 nM CaM. We conclude that CaM is essential for dantrolene inhibition of RyR1 and RyR2. Its absence explains why dantrolene inhibition of single RyR channels has not been previously observed.

Footnotes

    • Received January 1, 2015.
    • Accepted April 28, 2015.
  • This work was funded by a New South Wales Health Infrastructure grant through the Hunter Medical Research Institute to D.R.L.; the National Health and Medical Research Council Project [Grant APP 1005974] to D.R.L. and B.C.K.; National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL88635] to B.C.K.; and an American Heart Association Innovative Research Grant [13IRG13680003] to B.C.K.

  • The authors declare that there is no conflict of interest in this report.

  • dx.doi.org/10.1124/mol.115.097691.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (1)
Molecular Pharmacology
Vol. 88, Issue 1
1 Jul 2015
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Research ArticleArticle

Dantrolene Inhibition Requires Calmodulin

Ye Win Oo, Nieves Gomez-Hurtado, Kafa Walweel, Dirk F. van Helden, Mohammad S. Imtiaz, Bjorn C. Knollmann and Derek R. Laver
Molecular Pharmacology July 1, 2015, 88 (1) 57-63; DOI: https://doi.org/10.1124/mol.115.097691

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Research ArticleArticle

Dantrolene Inhibition Requires Calmodulin

Ye Win Oo, Nieves Gomez-Hurtado, Kafa Walweel, Dirk F. van Helden, Mohammad S. Imtiaz, Bjorn C. Knollmann and Derek R. Laver
Molecular Pharmacology July 1, 2015, 88 (1) 57-63; DOI: https://doi.org/10.1124/mol.115.097691
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