Regulation of RYR2 by sarcoplasmic reticulum Ca 2+

Summary Ca 2+ is arguably the most important ion involved in the contraction of the heart. The cardiac ryanodine receptor (RyR2), the major Ca 2+ release channel located in the sarcoplasmic reticulum (SR) membrane, is responsible for releasing the bulk of Ca 2+ required for contraction. Moreover, RyR2 is also crucial for maintaining SR Ca 2+ homeostasis by releasing Ca 2+ from the SR when it becomes overloaded with Ca 2+ . During normal contraction, RyR2 is activated by cytosolic Ca 2+ , whereas during store overload conditions, the opening of RyR2 is governed by SR Ca 2+ . Although the process of the cytosolic control of RyR2 is well established, the molecular mechanism by which SR luminal Ca 2+ regulates RyR2 has only recently been elucidated and remains controversial. In addition to the activation of RyR2, SR luminal Ca 2+ also determines when the RyR2 channel closes. RyR2‐mediated Ca 2+ release from the SR does not continue until the SR is completely depleted. Rather, it ceases when SR luminal Ca 2+ falls below a certain level. Given the importance of SR Ca 2+ , it is not surprising that the SR luminal Ca 2+ level is tightly controlled by SR Ca 2+ ‐buffering proteins. Consequently, the opening and closing of RyR2 is heavily influenced by the presence of such proteins, particularly those associated with RyR2, such as calsequestrin and the histidine‐rich Ca 2+ ‐binding protein. These proteins appear to indirectly alter RyR2 activity by modifying the microdomain SR Ca 2+ level surrounding RyR2.