Jgp_201711847 833..836

Every time the heart beats, increases and decreases in cytosolic free Ca ([Ca]cyto) switch on and off the mechanochemical reaction that produces movement and force. These [Ca]cyto transients are generated by the interplay of several different mechanisms, including (1) Ca entry into the cell (largely via CaV1.2 channels), (2) Ca release from the SR (a specialized intracellular organelle), and (3) cytosolic Ca removal processes (i.e., various pumps and ion exchangers) that extrude Ca from the cell or return it back into the SR. Mitochondrial Ca stores, and various other organelles and Ca-binding molecules, also contribute (Bers, 2001). However, the primary source of the transient rise in [Ca]cyto is release from the SR. The following five Perspective articles focus on the control of Ca release from within the SR and, in particular, the mechanisms whereby cardiac SR Ca release is altered by changes in [Ca]SR. The articles reveal that this crucial function is indeed dynamically modulated by the changing contents of the store and that multiple mechanisms are at work in the modulation, even if their respective impacts remain controversial. Ca release from the SR occurs at discrete sites (i.e., Ca release units [CRUs]) and is mediated by RyR2 channels deployed in specialized SR junctional membranes, called the terminal cisternae. The term “couplon” (Stern et al., 1997, 1999; Franzini-Armstrong et al., 1999), which refers to the set of proteins that work in interaction, conveys the idea that the device operating here comprises multiple channels (CaVs and RyRs) and various closely associated molecules, the concerted function of which defines the duration and magnitude of the local Ca flux. The RyR channels bridge two compartments with markedly different Ca regimens. The SR is a small-volume Ca storage compartment, where resting free [Ca] is near 1 mM and where Ca buffering has high capacity and low affinity. The cytosol is instead a compartment of much larger volume, where the free [Ca] is four orders of magnitude lower and buffering has multiple sites, affinities, and kinetic rates. Because these regimens are so different, a well-behaved system would benefit from control by dual sensors—a “toe” in each compartment—to monitor, feedback, and modulate the system accordingly. The cytosolic sensor would have to react to small and rapid Ca stimuli, whereas the intra-SR (luminal) sensor should be tuned to detect Ca depletion. Nature does even better. The RyR channel actually has multiple sensors in each compartment, all of which react differently to local Ca changes to govern the degree by which RyRs open. Closed RyRs open when Ca binds to a site, now apparently identified (des Georges et al., 2016), on the cytosolic side on the RyR protein. The triggering Ca signal normally arises first from voltage-dependent CaV1.2 channels in the plasma membrane and is then reinforced by Ca from open RyRs. The result is Ca-induced Ca release, or CICR (Fabiato, 1983; Näbauer et al., 1989). Another Ca-binding site on the cytosolic side of the RyR mediates Cadependent inactivation, or CDI, which appears to be more marked in skeletal muscle than in the heart (Meissner et al., 1986; Fill and Copello, 2002). Additionally, several lines of evidence appear to show that the RyR channel also reacts to luminal Ca concentration ([Ca]SR) changes (e.g., Terentyev et al., 2003; Jiang et al., 2007; Laver, 2007). The mechanisms by which Ca release from the SR is controlled are important for normal heart function. To begin with, every heartbeat requires a cytosolic Ca transient of finite duration; therefore, CICR must reliably terminate. Isn’t this termination dictated simply by the finite duration of the action potential, which turns on and off the Ca entry into the cells that triggers RyR opening during systole? Not really. Researchers have long identified the possibility that Ca release from open RyR channels will feed back positively, on the same channels or its neighbors, in a self-sustaining and potentially explosive process. Therefore, some CICR termination mechanism or mechanisms must exist, although there is no agreement as to their nature. Insufficient termination will not just distort the immediate