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Functional Impact of Ryanodine Receptor Oxidation on Intracellular Calcium Regulation in the Heart

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Reviews of Physiology, Biochemistry and Pharmacology, Vol. 171

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 171))

Abstract

Type 2 ryanodine receptor (RyR2) serves as the major intracellular Ca2+ release channel that drives heart contraction. RyR2 is activated by cytosolic Ca2+ via the process of Ca2+-induced Ca2+ release (CICR). To ensure stability of Ca2+ dynamics, the self-reinforcing CICR must be tightly controlled. Defects in this control cause sarcoplasmic reticulum (SR) Ca2+ mishandling, which manifests in a variety of cardiac pathologies that include myocardial infarction and heart failure. These pathologies are also associated with oxidative stress. Given that RyR2 contains a large number of cysteine residues, it is no surprise that RyR2 plays a key role in the cellular response to oxidative stress. RyR’s many cysteine residues pose an experimental limitation in defining a specific target or mechanism of action for oxidative stress. As a result, the current understanding of redox-mediated RyR2 dysfunction remains incomplete. Several oxidative modifications, including S-glutathionylation and S-nitrosylation, have been suggested playing an important role in the regulation of RyR2 activity. Moreover, oxidative stress can increase RyR2 activity by forming disulfide bonds between two neighboring subunits (intersubunit cross-linking). Since intersubunit interactions within the RyR2 homotetramer complex dictate the channel gating, such posttranslational modification of RyR2 would have a significant impact on RyR2 function and Ca2+ regulation. This review summarizes recent findings on oxidative modifications of RyR2 and discusses contributions of these RyR2 modifications to SR Ca2+ mishandling during cardiac pathologies.

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Acknowledgments

This work was supported by the NIH Grant (R01HL130231), the Research Career Development Award from the Schweppe Foundation, and the RFC grant from Loyola University Chicago to A.V.Z.

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Authors and Affiliations

  1. Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, IL, 60153, USA

    Aleksey V. Zima & Stefan R. Mazurek

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  1. Aleksey V. Zima
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  2. Stefan R. Mazurek
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Correspondence to Aleksey V. Zima .

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Editors and Affiliations

  1. KU Leuven, Leuven, Belgium

    Bernd Nilius

  2. Cardiovascular Research Center, Loyola University Chicago, Maywood, Illinois, USA

    Pieter de Tombe

  3. Walther-Straub-Institut für Pharmakologie und Toxikologie, München, Bayern, Germany

    Thomas Gudermann

  4. Department of Neurobiology, Max-Planck-Institute, Göttingen, Niedersachsen, Germany

    Reinhard Jahn

  5. Department of Cytobiology, University of Marburg, Marburg, Germany

    Roland Lill

  6. Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom

    Ole H. Petersen

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Zima, A.V., Mazurek, S.R. (2016). Functional Impact of Ryanodine Receptor Oxidation on Intracellular Calcium Regulation in the Heart. In: Nilius, B., de Tombe, P., Gudermann, T., Jahn, R., Lill, R., Petersen, O. (eds) Reviews of Physiology, Biochemistry and Pharmacology, Vol. 171. Reviews of Physiology, Biochemistry and Pharmacology, vol 171. Springer, Cham. https://doi.org/10.1007/112_2016_2

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