Jgp_201711814 847..856

Introduction In all types of muscle cells, contraction is initiated by an increase in intracellular Ca. Another similarity among skeletal, cardiac, and smooth muscle cells is that much of the Ca responsible for contraction is released from the SR. Beyond these common features, however, molecular and subcellular differences among muscle types can frequently explain functional differences. For instance, SR Ca release in cardiac myocytes occurs primarily through the type 2 RyR (RyR2), whereas different release channels are more important in other cell types. Another relevant feature in heart is that cells must contract and relax roughly once per second or faster. Thus, although skeletal and smooth muscle may experience either brief or sustained elevations of intracellular [Ca], rhythmic and regular heartbeats in cardiac myocytes result in continuous oscillations in intracellular [Ca], accompanied by regular dynamic changes in SR [Ca]. These concentration changes in the two compartments have been shown in recent years to convey information and regulate the release process. In this Perspective, we aim to review what has been learned about the regulatory importance of cardiac SR [Ca] and establish some constraints on plausible ranges for changes in SR [Ca] during release. In doing so, we emphasize how close coupling between experimental studies and numerical simulations has improved our understanding, and we discuss the importance of the interplay between SR [Ca] and diastolic [Ca] in the transition between stable and unstable cellular Ca release. In particular, we argue that increased diastolic [Ca] can raise RyR2 open probability in a manner that is potentially dangerous when combined with elevated SR [Ca].