S-nitrosylation of the Ryanodine Receptor (Calcium Channels)
S-nitrosylation describes the covalent attachment of an NO compound to a reactive thiol on cysteine side chains of proteins resulting in their posttransitional modificiation. Often such modifications include changes in both structure and function of the protein (Casadei et al., 2008).
Leaky calcium channels can be induced by increasing the opening of the Ryanodine receptor (RYR2) during diastole resulting in a decrease in SR Ca2+ and in the amplitude of the Ca2+ transient. These factors lead to decreased inotropy and often heart failure. In 1997, Stoyanovsky showed that exogeneous NO applied to S-nitroso-N-acetyl penicillamine increased the open potential (Popen) of the ryanodine receptor (Casadei et al., 2008). The open potential of the receptor describes the probability that the receptor will be in an open conformation and cause an undesirable release of Ca2+. More recently Kai Y Xu, (University of Maryland School of Medicine) introduced the NO donor S-nitrosoglutathione (GSNO) to the ryanodine receptor in planar lipid bilayers, results suggest that constitutive S-nitrosylation of the ryanodine receptor can alter channel open probability under physiological conditions. Increasing the number of S-nitrosylated thiol sites per RyR2 induced a similar increase in Popen increasing the chance of calcium leakage from the channel (Casadei et al., 2008).
Nitric oxide, an important signaling molecule in mammals, functions as a vasodialator both directly and indirectly and also employs an anti-thrombotic and anti-inflammatory effect, and it inhibits smooth muscle cell proliferation. A reduction in nitric oxide results in vasoconstriction, thrombosis, inflammation and increased size of vascular cells which all contribute to heart failure (Casadei et al., 2008).