Functional Impact of Ryanodine Receptor Oxidation on Intracellular Calcium Regulation in the Heart.
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.
['Zima|Aleksey V|AV|', 'Mazurek|Stefan R|SR|']
D000818:Animals D002118:Calcium D006333:Heart Failure D006801:Humans D009200:Myocardial Contraction D015428:Myocardial Reperfusion Injury D009206:Myocardium D018384:Oxidative Stress D019837:Ryanodine Receptor Calcium Release Channel D012519:Sarcoplasmic Reticulum
Ryanodine receptor Heart Sarcoplasmic reticulum Ca release Glutathione Reactive oxygen species