title: Functional Impact of Ryanodine Receptor Oxidation on Intracellular Calcium Regulation in the Heart.
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.
authors.affiliation: Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, IL, 60153, USA. azima@luc.edu.
authors.forename: Aleksey V
authors.initials: AV
authors.lastname: Zima
authors.affiliation: Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, IL, 60153, USA.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Mazurek
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
keywords: Ca release; Glutathione; Heart; Reactive oxygen species; Ryanodine receptor; Sarcoplasmic reticulum