Regulation of RyR Channel Gating by Ca 2+ , Mg 2+ and ATP

This chapter discusses the regulation of calcium release channels—ryanodine receptors (RyRs)—in the sarcoplasmic reticulum (SR) by intracellular ligands. It focuses on Ca 2+, Mg 2+, and ATP that are the key regulators of the RyR. Different RyR isoforms are expressed in skeletal and cardiac muscle. These isoforms are modulated differently by Ca 2+, Mg 2+, and ATP, leading to the different characteristics of excitation–contraction (E–C) coupling in the two muscle types. The chapter describes a kinetic model for RyR2 gating that permits prediction of the role of Ca 2+, Mg 2+, and ATP microdomains in stimulating RyR activity and SR Ca 2+ release during cardiac E–C coupling. Stimulation of Ca 2+ release in cardiac cells can be induced by Ca 2+ binding to either the luminal (L-site) or cytoplasmic (A-site) of RyR2. These different modes of RyR2-activation are likely to serve quite different functions in the heart. At the beginning of diastole, the RyRs in the heart are inactive because the SR is depleted of Ca 2+ and the cytoplasmic Ca 2+ has returned to resting levels. The model predicts that under these conditions, the A- and L-sites of the RyRs are mostly occupied by [Mg 2+ ]. According to this model, the degree of Ca 2+ loading of the SR is an important regulator of the SR Ca 2+ leak during diastole however it has no significant effect on RyR2 gating during systole.