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Mechanisms of Disease: ryanodine receptor defects in heart failure and fatal arrhythmia

Nature Clinical Practice Cardiovascular Medicine volume 3, pages 43–52 (2006)Cite this article

Abstract

Abnormal regulation of intracellular Ca2+ by sarcoplasmic reticulum plays a part in the mechanism underlying contractile and relaxation dysfunction in heart failure (HF). The protein-kinase-A-mediated hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum has been shown to cause the dissociation of FKBP12.6 (also known as calstabin-2) from ryanodine receptors in HF. In addition, several disease-linked mutations in the ryanodine receptors have been reported in patients with catecholaminergic polymorphic ventricular tachycardia or arrhythmogenic right ventricular cardiomyopathy type 2. The unique distribution of these mutation sites has led to the concept that the interaction among the putative regulatory domains within the ryanodine receptors has a key role in regulating channel opening. The knowledge gained from various studies of ryanodine receptors under pathologic conditions might lead to the development of new pharmacological or genetic strategies for the treatment of HF or cardiac arrhythmia. In this review, we focus on the role of the Ca2+-release channel, the ryanodine receptor, in the pathogenesis of HF and fatal arrhythmia, and the possibility of developing new therapeutic strategies for targeting this receptor.

Key Points

  • Alterations in calcium ion (Ca2+) cycling can cause depression of mechanical performance of the heart

  • The calcium-release channel, the ryanodine receptor (RyR)2, seems to have a notable role in heart failure and fatal arrhythmia

  • Hyperphosphorylation of RyRs in the sarcoplasmic reticulum leads to abnormal intracellular Ca2+ concentrations, which contribute to contractile and relaxation dysfunction in heart failure

  • Several disease-linked mutations in the RyRs linked to regulatory domains have been implicated in the altered regulation of channel opening

  • RyR2 might prove to be a useful therapeutic target

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Figure 1: Structural domains of the cardiac ryanodine receptor and satellite proteins.
Figure 2: Disease-linked mutation sites on ryanodine receptors 1 and 2.
Figure 3: Channel stabilization of ryanodine receptor 2 by β-blockers and angiotensin-II-receptor antagonists.
Figure 4: Schematic diagram of domain–domain interaction within the ryanodine receptor as a new therapeutic target.

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Acknowledgements

This work was supported by grants-in-aid for scientific research from The Ministry of Education in Japan to M Yano and M Matsuzaki, by grants from the Takeda Science Foundation to T Yamamoto and Y Ikeda, and by the Japan Heart Foundation/Pfizer Japan Inc. Grant for Research on Cardiovascular Disease to T Yamamoto.

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Authors and Affiliations

  1. an Assistant Professor, Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan

    Masafumi Yano

  2. Research Associates, Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan

    Takeshi Yamamoto & Yasuhiro Ikeda

  3. a Professor, in the Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan

    Masunori Matsuzaki

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  1. Masafumi Yano
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Correspondence to Masunori Matsuzaki.

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Yano, M., Yamamoto, T., Ikeda, Y. et al. Mechanisms of Disease: ryanodine receptor defects in heart failure and fatal arrhythmia. Nat Rev Cardiol 3, 43–52 (2006). https://doi.org/10.1038/ncpcardio0419

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