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Reply to ‘Mechanisms of ryanodine receptor 2 dysfunction in heart failure’

Nature Reviews Cardiology volume 17, pages 749–750 (2020)Cite this article

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We appreciate that Francisco J. Alvarado and Héctor H. Valdivia write in their Correspondence (Mechanisms of ryanodine receptor 2 dysfunction in heart failure. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-00443-x (2020))1 that they agree with the fundamental premise of our Review (Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-0394-8 (2020))2 on the causal role of intracellular Ca2+ leak in cardiovascular arrhythmias. However, they take issue with our discussion of the mechanistic role of cAMP-dependent protein kinase (PKA) phosphorylation of Ser2808 in the ryanodine receptor 2 (RYR2) in heart failure (HF) progression3 and claim that our findings have not been reproduced by others. We disagree. Indeed, as we show below, data from the Valdivia laboratory provide proof of the reproducibility of our results.

Our Review2 summarizes the mechanisms that impair regulation of the Ca2+-release channel, RYR2, and how they contribute to HF and atrial fibrillation (AF). We provide an overview of how inherited genetic variants and stress-induced phosphorylation and oxidation of RYR2 cause dissociation of the RYR2-stabilizing protein calstabin 2 (also known as FK506-binding protein 12.6) and a pathological diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) that triggers arrhythmias and impairs cardiac contractility3.

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Fig. 1: Intracellular Ca2+ transients and contractions in WT and RYR2-Ser2808Ala cardiomyocytes.

References

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Authors and Affiliations

  1. Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

    Haikel Dridi, Alexander Kushnir, Qi Yuan, Zephan Melville & Andrew R. Marks

  2. The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel

    Ran Zalk

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  1. Haikel Dridi
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Correspondence to Andrew R. Marks.

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Competing interests

A.R.M. and Columbia University, USA, own shares in ARMGO Pharma, a biotechnology company developing ryanodine receptor-targeted drugs. The other authors declare no competing interests.

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Dridi, H., Kushnir, A., Zalk, R. et al. Reply to ‘Mechanisms of ryanodine receptor 2 dysfunction in heart failure’. Nat Rev Cardiol 17, 749–750 (2020). https://doi.org/10.1038/s41569-020-00444-w

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