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Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations

Author

Listed:
  • Takuya Kobayashi

    (Juntendo University Graduate School of Medicine)

  • Akihisa Tsutsumi

    (The University of Tokyo)

  • Nagomi Kurebayashi

    (Juntendo University Graduate School of Medicine)

  • Kei Saito

    (The University of Tokyo)

  • Masami Kodama

    (Juntendo University Graduate School of Medicine)

  • Takashi Sakurai

    (Juntendo University Graduate School of Medicine)

  • Masahide Kikkawa

    (The University of Tokyo)

  • Takashi Murayama

    (Juntendo University Graduate School of Medicine)

  • Haruo Ogawa

    (Kyoto University)

Abstract

Cardiac ryanodine receptor (RyR2) is a large Ca2+ release channel in the sarcoplasmic reticulum and indispensable for excitation-contraction coupling in the heart. RyR2 is activated by Ca2+ and RyR2 mutations are implicated in severe arrhythmogenic diseases. Yet, the structural basis underlying channel opening and how mutations affect the channel remains unknown. Here, we address the gating mechanism of RyR2 by combining high-resolution structures determined by cryo-electron microscopy with quantitative functional analysis of channels carrying various mutations in specific residues. We demonstrated two fundamental mechanisms for channel gating: interactions close to the channel pore stabilize the channel to prevent hyperactivity and a series of interactions in the surrounding regions is necessary for channel opening upon Ca2+ binding. Mutations at the residues involved in the former and the latter mechanisms cause gain-of-function and loss-of-function, respectively. Our results reveal gating mechanisms of the RyR2 channel and alterations by pathogenic mutations at the atomic level.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30429-x
    DOI: 10.1038/s41467-022-30429-x
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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. 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.
    3. Zhen Yan & Xiao-chen Bai & Chuangye Yan & Jianping Wu & Zhangqiang Li & Tian Xie & Wei Peng & Chang-cheng Yin & Xueming Li & Sjors H. W. Scheres & Yigong Shi & Nieng Yan, 2015. "Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution," Nature, Nature, vol. 517(7532), pages 50-55, January.
    4. 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.
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