**Acknowledgements**

and hence contractility. The advanced glycation of SERCA2a has been shown to lead to a

Recently, attention has been focused on abnormalities of calcium release in diabetic conditions. In diabetic subjects, oxidative stress arises from an imbalance between production of reactive oxygen and nitrogen species and capability of the system to readily detoxify reactive inter‐ mediates. Importantly, it is now well established that RyR channels are highly susceptible to modification by various endogenous redox agents. Furthermore, RyR channels serve a role as intracellular redox sensors, via redox induced Ca2+ release and they are likely to connect cellular redox state with Ca2+ signaling cascades. Indeed, endogenous redox active molecules enhance RyR2 channel activity and RyR2 is one of the well-characterized redox-sensitive ion channels in heart. In general, oxidizing conditions increase RyR2 activity and so stimulate SR Ca2+ and causing Ca2+ leak (*see figure 3)*. In addition, RyR2 is activated also by reactive nitrogen species and S-nitrosylation increases RyR open probability in cardiac muscle and leads to increased Ca2+ leak [14]. Redox reactions by biological oxidants and antioxidants have been shown to alter the kinetics of Ca2+-induced Ca2+ release in the heart tissue. Besides several potential phosphorylation sites, the tetrameric RyR2 channel contains ~84 free thiols and is Snitrosylated in vivo. S-Nitrosylation of up to 12 sites (3 per subunit) led to progressive channel activation that was reversed by denitrosylation. RyR2 is activated also by reactive nitrogen species. For example, nNOS is expressed in SR and can supply NO to RyR2 in the immediate vicinity for S-nitrosylation, which increases RyR2 open probability in cardiac muscle and leads to increased Ca2+ release. Thus, sulfydryl-oxidizing agents, hydrogen peroxide and diamide,

**Figure 3.** Intracellular calcium regulation and influence of oxidizing molecules (ROS, reactive oxygen species; RNS, re‐

decrease in its activity and a prolongation of cardiac relaxation [14].

diminished RyR2-FKBP12.6 binding [90].

254 Cardiomyopathies

active nitrogen species) on RyR2 function.

This article was supported by the grant EFSD New Horizons 2012 *The role of HGF/c-Met signalling in diabetic end-organ damage* from the European Foundation for the Study of Diabetes - New Horizons, Collaborative Research Initiative and the grant APVV-0887-11 *Molecular aspects of drug induced heart failure and ventricular arrhythmias* from the Slovak Research and Development Agency.
