FIGURE 2.
Oxidative stress is associated with the increased accumulation of reactive oxygen and nitrogen species (ROS/RNS), such as O2-●, H2O2, OH●, and ONOO-●. ROS and RNS have been implicated in redox-dependent post-translational modifications of cardiac RyR2, including S-glutathionylation, S-nitrosylation and disulfide bond formation (marked with solid arrows). Disulfide bond formation also leads to RyR2 cross-linking, which presumably may take place between subunits within one channel or between subunits of different channels. Oxidative stress may also indirectly modulate the activity of RyR2 (marked dashed arrows). Accumulation of ROS/RNS leads to calmodulin (CaM) dissociation from RyR2, potentially caused by the oxidation of RyR2 and/or CaM. Oxidative stress can also activate PKA and CaMKII leading to an increase of RyR2 phosphorylation on Serine 2808 and Serine 2814 sites. It has been also suggested that the PKA-dependent phosphorylation may lead to increased FKBP12.6 dissociation from RyR2. The effects of oxidative stress on RyR2 mostly lead to the increased diastolic SR Ca leak resulting in arrhythmias and contractile dysfunction in variety of cardiac pathologies.