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Modulation of cardiac ryanodine receptor 2 by calmodulin

Author

Listed:
  • Deshun Gong

    (Tsinghua University)

  • Ximin Chi

    (Tsinghua University)

  • Jinhong Wei

    (University of Calgary)

  • Gewei Zhou

    (Tsinghua University)

  • Gaoxingyu Huang

    (Tsinghua University)

  • Lin Zhang

    (University of Calgary)

  • Ruiwu Wang

    (University of Calgary)

  • Jianlin Lei

    (Tsinghua University)

  • S. R. Wayne Chen

    (University of Calgary)

  • Nieng Yan

    (Tsinghua University
    Princeton University)

Abstract

The high-conductance intracellular calcium (Ca2+) channel RyR2 is essential for the coupling of excitation and contraction in cardiac muscle. Among various modulators, calmodulin (CaM) regulates RyR2 in a Ca2+-dependent manner. Here we reveal the regulatory mechanism by which porcine RyR2 is modulated by human CaM through the structural determination of RyR2 under eight conditions. Apo-CaM and Ca2+-CaM bind to distinct but overlapping sites in an elongated cleft formed by the handle, helical and central domains. The shift in CaM-binding sites on RyR2 is controlled by Ca2+ binding to CaM, rather than to RyR2. Ca2+-CaM induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95 and Ca2+-activated channel. By contrast, the pore of the ATP, caffeine and Ca2+-activated channel remains open in the presence of Ca2+-CaM, which suggests that Ca2+-CaM is one of the many competing modulators of RyR2 gating.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:572:y:2019:i:7769:d:10.1038_s41586-019-1377-y
    DOI: 10.1038/s41586-019-1377-y
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    Citations

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    Cited by:

    1. 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.
    2. Robyn T. Rebbeck & Bengt Svensson & Jingyan Zhang & Montserrat Samsó & David D. Thomas & Donald M. Bers & Razvan L. Cornea, 2024. "Kinetics and mapping of Ca-driven calmodulin conformations on skeletal and cardiac muscle ryanodine receptors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. 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.
    4. Takuya Kobayashi & Akihisa Tsutsumi & Nagomi Kurebayashi & Kei Saito & Masami Kodama & Takashi Sakurai & Masahide Kikkawa & Takashi Murayama & Haruo Ogawa, 2022. "Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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