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Research ArticleArticle

Multiple Actions of the Anthracycline Daunorubicin on Cardiac Ryanodine Receptors

Amy D. Hanna, Marie Janczura, Eric Cho, Angela F. Dulhunty and Nicole A. Beard
Molecular Pharmacology September 2011, 80 (3) 538-549; DOI: https://doi.org/10.1124/mol.111.073478
Amy D. Hanna
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Marie Janczura
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Eric Cho
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Angela F. Dulhunty
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Nicole A. Beard
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Abstract

Our aim was to examine the molecular basis for acute effects of the anthracycline daunorubicin on cardiac ryanodine receptor (RyR2) channels and cardiac calsequestrin (CSQ2). Cardiotoxic effects of anthracyclines preclude their chemotherapeutic use in patients with pre-existing heart conditions. To address this significant problem, the mechanisms of anthracycline toxicity must be defined but at present are poorly understood. RyR2 channel activity was assessed by measuring Ca2+ release from cardiac sarcoplasmic reticulum vesicles and by examining single RyR2 channels inserted into artificial lipid bilayers. We show that 0.5 to 10 μM daunorubicin increases the activity of RyR2 channels after 5 to 10 min and that activity then declines to very low levels when channels are exposed to daunorubicin concentrations of ≥2.5 μM for a further 10 to 20 min. Extensive dissection of these effects shows for the first time that the activation results from a redox-independent binding of daunorubicin to the RyR2 complex. Novel data include the demonstration of daunorubicin binding to RyR2. We provide compelling evidence that RyR2 channel inhibition is due to the oxidation of free SH groups. The oxidation reaction is prevented by the presence of 1 mM dithiothreitol. We also present novel data showing that CSQ2 modifies the response of RyR2 to daunorubicin, but that the response of RyR2 is not dependent on daunorubicin binding to CSQ2. We suggest that binding of daunorubicin to RyR2 and CSQ2, and oxidation of RyR2, are all likely to contribute to anthracycline-induced cardiotoxicity during chemotherapy.

Footnotes

  • A.F.D. and N.A.B. made equal senior author contributions to the work.

  • This work was supported by the Australian National Health and Medical Research Council [Grants 471400, 1003985].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.073478.

  • ABBREVIATIONS:

    SR
    sarcoplasmic reticulum
    RyR
    ryanodine receptor
    RyR1
    skeletal isoform of the ryanodine receptor (ryanodine receptor type 1)
    RyR2
    cardiac isoform of the ryanodine receptor (ryanodine receptor type 2)
    CSQ2
    cardiac isoform of calsequestrin (calsequestrin type 2)
    SERCA
    sarcoplasmic endoplasmic reticulum Ca2+ ATPase
    DTT
    dithiothreitol
    TEMED
    N,N,N′,N′-tetramethylethylenediamine
    TES
    N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    Po
    open probability
    I′F
    fractional mean current
    A23187
    calcimycin
    PoD
    channel open probability with daunorubicin
    PoC
    control channel open probability
    NEM
    N-ethylmaleimide
    EAD
    early after-depolarization.

  • Received May 8, 2011.
  • Accepted June 21, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

Multiple Actions of the Anthracycline Daunorubicin on Cardiac Ryanodine Receptors

Amy D. Hanna, Marie Janczura, Eric Cho, Angela F. Dulhunty and Nicole A. Beard
Molecular Pharmacology September 1, 2011, 80 (3) 538-549; DOI: https://doi.org/10.1124/mol.111.073478

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Research ArticleArticle

Multiple Actions of the Anthracycline Daunorubicin on Cardiac Ryanodine Receptors

Amy D. Hanna, Marie Janczura, Eric Cho, Angela F. Dulhunty and Nicole A. Beard
Molecular Pharmacology September 1, 2011, 80 (3) 538-549; DOI: https://doi.org/10.1124/mol.111.073478
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