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Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders

Author

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  • Marco C. Miotto

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Steven Reiken

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Anetta Wronska

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Qi Yuan

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Haikel Dridi

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Yang Liu

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Gunnar Weninger

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Carl Tchagou

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

  • Andrew R. Marks

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University)

Abstract

Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca2+ leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca2+ leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca2+ leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders.

Suggested Citation

  • Marco C. Miotto & Steven Reiken & Anetta Wronska & Qi Yuan & Haikel Dridi & Yang Liu & Gunnar Weninger & Carl Tchagou & Andrew R. Marks, 2024. "Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51791-y
    DOI: 10.1038/s41467-024-51791-y
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    References listed on IDEAS

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    1. Deshun Gong & Ximin Chi & Jinhong Wei & Gewei Zhou & Gaoxingyu Huang & Lin Zhang & Ruiwu Wang & Jianlin Lei & S. R. Wayne Chen & Nieng Yan, 2019. "Modulation of cardiac ryanodine receptor 2 by calmodulin," Nature, Nature, vol. 572(7769), pages 347-351, August.
    2. Donald M. Bers, 2002. "Cardiac excitation–contraction coupling," Nature, Nature, vol. 415(6868), pages 198-205, January.
    3. Kellie A. Woll & Omid Haji-Ghassemi & Filip Van Petegem, 2021. "Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. Ali Dashti & Ghoncheh Mashayekhi & Mrinal Shekhar & Danya Ben Hail & Salah Salah & Peter Schwander & Amedee des Georges & Abhishek Singharoy & Joachim Frank & Abbas Ourmazd, 2020. "Retrieving functional pathways of biomolecules from single-particle snapshots," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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