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Cysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR)

Author

Listed:
  • Roman Nikolaienko

    (Loyola University Chicago)

  • Elisa Bovo

    (Loyola University Chicago)

  • Daniel Kahn

    (Loyola University Chicago)

  • Ryan Gracia

    (Loyola University Chicago)

  • Thomas Jamrozik

    (Loyola University Chicago)

  • Aleksey V. Zima

    (Loyola University Chicago)

Abstract

The most common cardiac pathologies, such as myocardial infarction and heart failure, are associated with oxidative stress. Oxidation of the cardiac ryanodine receptor (RyR2) Ca2+ channel causes spontaneous oscillations of intracellular Ca2+, resulting in contractile dysfunction and arrhythmias. RyR2 oxidation promotes the formation of disulfide bonds between two cysteines on neighboring RyR2 subunits, known as intersubunit cross-linking. However, the large number of cysteines in RyR2 has been a major hurdle in identifying the specific cysteines involved in this pathology-linked post-translational modification of the channel. Through mutagenesis of human RyR2 and in-cell Ca2+ imaging, we identify that only two cysteines (out of 89) in each RyR2 subunit are responsible for half of the channel’s functional response to oxidative stress. Our results identify cysteines 1078 and 2991 as a redox-sensitive pair that forms an intersubunit disulfide bond between neighboring RyR2 subunits during oxidative stress, resulting in a pathological “leaky” RyR2 Ca2+ channel.

Suggested Citation

  • Roman Nikolaienko & Elisa Bovo & Daniel Kahn & Ryan Gracia & Thomas Jamrozik & Aleksey V. Zima, 2023. "Cysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR)," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40268-z
    DOI: 10.1038/s41467-023-40268-z
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    References listed on IDEAS

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    1. Junji Suzuki & Kazunori Kanemaru & Kuniaki Ishii & Masamichi Ohkura & Yohei Okubo & Masamitsu Iino, 2014. "Imaging intraorganellar Ca2+ at subcellular resolution using CEPIA," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
    2. 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.
    3. Donald M. Bers, 2002. "Cardiac excitation–contraction coupling," Nature, Nature, vol. 415(6868), pages 198-205, January.
    4. Ching-Chieh Tung & Paolo A. Lobo & Lynn Kimlicka & Filip Van Petegem, 2010. "The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule," Nature, Nature, vol. 468(7323), pages 585-588, November.
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