Ambiguous interactions between diastolic and SR Ca2+ in the regulation of cardiac Ca2+ release

Figure 1.. Hypothetical changes in SR and cytosolic [Ca2+] during SR release. (A) An increase in the fraction of total SR Ca2+ released causes a decrease in SR free [Ca2+] and a corresponding increase in cytosolic free [Ca2+]. Curves are nonlinear because of the presence of Ca2+ buffers in each compartment. Calculations assumed: (1) SR [Ca2+] and cytosolic [Ca2+] were 1,000 µM and 0.1 µM, respectively, before release; (2) cytosolic volume was 22.66 times larger than SR volume; (3) cytosolic buffering sites had maximal occupancy of 2,500 µM and a KD of 630 µM; (4) SR buffering sites had maximal occupancy of 220 µM and a KD of 0.96 µM. (B) Hypothetical profiles of SR [Ca2+] during release if Ca2+ diffusion within the SR is either extremely fast (blue) or quite slow (red). Because of blurring by confocal microscopes, attempts to record these SR [Ca2+] profiles are likely to yield similar values for the apparent extent of depletion.

Figure 2.. Contributions of increased SR and diastolic [Ca2+] to unstable Ca2+release. (A) Simulated line-scan images of typical stochastic simulations of Ca2+ sparks and waves. Simulations were performed with a mathematical model of Ca2+ release, as recently described (Wescott et al., 2016). The horizontal dimension represents time (1 s), and the vertical dimension represents transverse distance (14 µm). Labels indicate initial values of cytosolic and SR [Ca2+]. Each SR Ca2+ release unit contains a cluster of 50 stochastically gating RyR2s (see Wescott et al. [2016] for more details), and RyR2 clusters are randomly distributed, with a mean intersite distance of 700 nm. Large SR Ca2+ release events involving multiple RyR2 clusters are frequently observed when both SR [Ca2+] and diastolic [Ca2+] are increased (bottom right images). (B) Integrated RyR2 Ca2+release flux as a function of initial diastolic [Ca2+]i when initial SR [Ca2+] is either 1 mM (blue) or 1.5 mM (red). Flux is integrated over each 1-s simulation and averaged over 50 trials. Error bars show standard deviation.