Control of sarcoplasmic reticulum Ca2+ release by stochastic RyR gating within a 3D model of the cardiac dyad and importance of induction decay for CICR termination

The factors responsible for the regulation of regenerative calcium-induced calcium release (CICR) during Ca2þ spark evolution remain unclear. Cardiac ryanodine receptor (RyR) gating in rats and sheep was recorded at physiological Ca2þ, Mg2þ, and ATP levels and incorporated into a 3D model of the cardiac dyad, which reproduced the time course of Ca2þ sparks, Ca2þ blinks, and Ca2þ spark restitution. The termination of CICR by induction decay in the model principally arose from the steep Ca2þ dependence of RyR closed time, with the measured sarcoplasmic reticulum (SR) lumen Ca2þ dependence of RyR gating making almost no contribution. The start of CICR termination was strongly dependent on the extent of local deple- tion of junctional SR Ca2þ, as well as the time course of local Ca2þ gradients within the junctional space. Reducing the dimen- sions of the dyad junction reduced Ca2þ spark amplitude by reducing the strength of regenerative feedback within CICR. A refractory period for Ca2þ spark initiation and subsequent Ca2þ spark amplitude restitution arose from 1), the extent to which the regenerative phase of CICR can be supported by the partially depleted junctional SR, and 2), the availability of releasable Ca2þ in the junctional SR. The physical organization of RyRs within the junctional space had minimal effects on Ca2þ spark amplitude when more than nine RyRs were present. Spark amplitude had a nonlinear dependence on RyR single-channel Ca2þ flux, and was approximately halved by reducing the flux from 0.6 to 0.2 pA. Although rat and sheep RyRs had quite different Ca2þ sensitivities, Ca2þ spark amplitude was hardly affected. This suggests that moderate changes in RyR gating by second- messenger systems will principally alter the spatiotemporal properties of SR release, with smaller effects on the amount released.