Modeling Gain and Gradedness of Ca21 Release in the Functional Unit of the Cardiac Diadic Space

ABSTRACT A model of the functional release unit (FRU) in rat cardiac muscle consisting of one dihydropyridine receptor (DHPR) and eight ryanodine receptor (RyR) channels, and the volume surrounding them, is formulated. It is assumed that no spatial [Ca21] gradients exist in this volume, and that each FRU acts independently. The model is amenable to systematic parameter studies in which FRU dynamics are simulated at the channel level using Monte Carlo methods with Ca21 concentrations simulated by numerical integration of a coupled system of differential equations. Using stochastic methods, Ca21-induced Ca21 release (CICR) shows both high gain and graded Ca21 release that is robust when parameters are varied. For a single DHPR opening, the resulting RyR Ca21 release flux is insensitive to the DHPR open duration, and is determined principally by local sarcoplasmic reticulum (SR) Ca21 load, consistent with experimental data on Ca21 sparks. In addition, single RyR openings are effective in triggering Ca21 release from adjacent RyRs only when open duration is long and SR Ca21 load is high. This indicates relatively low coupling between RyRs, and suggests a mechanism that limits the regenerative spread of RyR openings. The results also suggest that adaptation plays an important modulatory role in shaping Ca21 release duration and magnitude, but is not solely responsible for terminating Ca21 release. Results obtained with the stochastic model suggest that high gain and gradedness can occur by the recruitment of independent FRUs without requiring spatial [Ca21] gradients within a functional unit or cross-coupling between adjacent functional units