Regulation of the Cardiac Muscle Ryanodine Receptor by O2 Tension and S-Nitrosoglutathione

The cardiac and skeletal muscle sarcoplasmic reticulum ryanodine receptor Ca2+ release channels contain thiols that are potential targets of endogenously produced reactive oxygen and nitrogen intermediates. Previously, we showed that the skeletal Muscle ryanodine receptor (RyR1) has O-2-sensitive thiols; only when these thiols are in the reduced state (pO(2) similar to 10 mmHg) can physiological concentrations of NO (nanomolar) activate RyR1. Here, we report that cardiac muscle ryanodine receptor (RyR2) activity also depends on pO(2) but unlike RyR1, RyR2 was not activated or S-nitrosylated directly by NO. Rather, activation and S-nitrosylation of RyR2 required S-nitrosoglutathione. The effects of peroxynitrite were indiscriminate on RYR1 and RyR2. Our results indicate that both RyR1 and RyR2 are pO(2)-responsive yet point to different mechanisms by which NO and S-ntrosoglutathione Influence cardiac and skeletal Muscle sarcoplasmic reticulum Ca2+ release.