Jgp_201711805 867..876

Introduction Cardiac myocyte contraction is driven by the coordinated release of Ca from the sarcoplasmic reticulum (SR). This release of Ca occurs through the cardiac RyR2. Physiologically, Ca release occurs in response to an influx of Ca through L-type Ca channels, via a mechanism termed CICR. This transient increase in cytosolic Ca activates the RyR2 channel as a result of Ca binding to the cytosolic Ca activation site of the channel (Bers, 2002). However, RyR2 is also known to be activated in the absence of cytosolic Ca elevation, under conditions of SR Ca overload. This phenomenon is commonly known as spontaneous Ca release, or store overload–induced Ca release (SOI CR), because of its dependence on SR Ca load (Jiang et al., 2004, 2005; Jones et al., 2008). SOI CR occurs when SR Ca content exceeds a threshold level, which can be caused by either an increase in SR Ca concentration higher than the threshold or a reduction in the threshold to a level less than the SR Ca concentration (Venetucci et al., 2007). Although SOI CR has been well characterized as an underlying mechanism of multiple pathologies (Jiang et al., 2004, 2005, 2008; Lehnart et al., 2008; Tang et al., 2012; Zhabyeyev et al., 2013), exactly how RyR2 detects and responds to SR luminal Ca has yet to be defined. Here we argue that SR luminal Ca is able to activate RyR2 via a luminal rather than a cytosolic site, and we discuss the functional evidence for this in light of recent structural information.