Control of Sarcoplasmic Reticulum Ca^sup 2+^ 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 Ca... spark evolution remain unclear. Cardiac ryanodine receptor (RyR) gating in rats and sheep was recorded at physiological Ca..., Mg..., and ATP levels and incorporated into a 3D model of the cardiac dyad, which reproduced the time course of Ca... sparks, Ca... blinks, and Ca... spark restitution. The termination of CICR by induction decay in the model principally arose from the steep Ca... dependence of RyR closed time, with the measured sarcoplasmic reticulum (SR) lumen Ca... dependence of RyR gating making almost no contribution. The start of CICR termination was strongly dependent on the extent of local depletion of junctional SR Ca..., as well as the time course of local Ca... gradients within the junctional space. Reducing the dimensions of the dyad junction reduced Ca... spark amplitude by reducing the strength of regenerative feedback within CICR. A refractory period for Ca... spark initiation and subsequent Ca... 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 Ca... in the junctional SR. The physical organization of RyRs within the junctional space had minimal effects on Ca... spark amplitude when more than nine RyRs were present. Spark amplitude had a nonlinear dependence on RyR single-channel Ca... flux, and was approximately halved by reducing the flux from 0.6 to 0.2 pA. Although rat and sheep RyRs had quite different Ca... sensitivities, Ca... 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. (ProQuest: ... denotes formulae/symbols omitted.)