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

  • Aleksey V. ZimaEmail author
  • Stefan R. Mazurek
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 171)


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.


Ca release Glutathione Heart Reactive oxygen species Ryanodine receptor Sarcoplasmic reticulum 



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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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Cell and Molecular PhysiologyLoyola University Chicago, Stritch School of MedicineMaywoodUSA

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