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The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias

Nature Medicine volume 20, pages 184–192 (2014)Cite this article

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Abstract

Spontaneous Ca2+ release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload–induced Ca2+ release (SOICR) can result in Ca2+ waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here we show that a point mutation, E4872A, in the helix bundle crossing region (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, Ca2+ activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni2+-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca2+-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca2+, explaining the regulation of RyR2 by luminal Ca2+, the initiation of Ca2+ waves and Ca2+-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms.

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Figure 1: The E4872A mutation abolishes luminal, but not cytosolic, Ca2+ activation of RyR2.
Figure 2: Effects of E4872A and E4872Q on cytosolic Ca2+ activation of single RyR2 channels.
Figure 3: Mechanism of activation of RyR2 by luminal Ca2+.
Figure 4: Effect of E4872 mutations on SOICR.
Figure 5: Effect of the E4872Q RyR2 mutation on EC coupling.
Figure 6: Heterozygous E4872Q mutant mice are resistant to SOICR-induced VTs.

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Acknowledgements

This work was supported by research grants from the Canadian Institutes of Health Research (CIHR) to H.J.D., D.P.T. and S.R.W.C., the US National Institutes of Health to J.C., L.-S.S., M.F. and S.R.W.C., the Heart and Stroke Foundation of Alberta to A.M.G., H.J.D. and S.R.W.C. and the Canada Foundation for Innovation (S.R.W.C.) and by the Heart and Stroke Foundation/Libin Cardiovascular Institute Professorship in Cardiovascular Research (S.R.W.C.). We are grateful for generous donations from the King family, the Howarth family and the Libin Cardiovascular Institute of Alberta. We are also grateful to W.C. Claycomb from the Louisiana State University Health Sciences Center for kindly providing the HL-1 cardiac cell line and to J. Lytton from the University of Calgary for the gift of the β-actin–specific antibody. W.C., X.Z. and X.T. are recipients of the Alberta Innovates-Health Solutions (AIHS) Studentship Award; P.P.J. is a recipient of AIHS and Heart and Stroke Foundation Fellowship Awards; M.L.O. is the recipient of a CIHR Fellowship Award; and H.J.D., D.P.T. and S.R.W.C. are recipients of AIHS Scientist Awards.

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  1. Yunlong Bai, Qiang Zhou, Cuihong Xie, Peter P Jones, Tao Mi & Hongqiang Cheng

    Present address: Present addresses: Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, China (Y.B.), Department of Cardiology of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Q.Z. and C.X.), Department of Physiology, University of Otago, Dunedin, New Zealand (P.P.J.), Department of Geriatrics of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (T.M.), and Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China (H.C.).,

Authors and Affiliations

  1. Department of Physiology and Pharmacology, The Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada

    Wenqian Chen, Ruiwu Wang, Xiaowei Zhong, Huihui Kong, Yunlong Bai, Qiang Zhou, Cuihong Xie, Xixi Tian, Peter P Jones, Yingjie Liu, Tao Mi, Lin Zhang, Jeff Bolstad, Lisa Semeniuk, Anne M Gillis, Henry J Duff & S R Wayne Chen

  2. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Biyi Chen, Ang Guo & Long-Sheng Song

  3. Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, USA

    Jingqun Zhang, Michael Fill & S R Wayne Chen

  4. Department of Biological Sciences and Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Alberta, Canada

    Megan L O'Mara & D Peter Tieleman

  5. Department of Medicine, University of California at San Diego, La Jolla, California, USA

    Hongqiang Cheng, Jianlin Zhang & Ju Chen

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W.C., R.W., B.C., X.Z., H.K., Y.B., Q.Z., A.G., X.T., P.P.J., M.L.O., J.C., D.P.T., A.M.G., H.J.D., M.F., L.-S.S. and S.R.W.C. designed research. W.C., R.W., B.C., X.Z., H.K., Y.B., Q.Z., C.X., Jingqun Zhang, A.G., X.T., P.P.J., M.L.O., Y.L., T.M., L.Z., J.B., L.S., H.C. and Jianlin Zhang performed research. W.C., R.W., Y.B., X.Z., H.K., Y.B., Q.Z., C.X., Jingqun Zhang, A.G., X.T., P.P.J., M.L.O., Y.L., T.M., L.Z., J.B., Jianlin Zhang, L.-S.S. and S.R.W.C. analyzed data. W.C., X.Z., Y.B., P.P.J., M.L.O., M.F., L.-S.S. and S.R.W.C. wrote the paper.

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Correspondence to S R Wayne Chen.

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Chen, W., Wang, R., Chen, B. et al. The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias. Nat Med 20, 184–192 (2014). https://doi.org/10.1038/nm.3440

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