Modeling gain and gradedness of Ca2+ release in the functional unit of thecardiac diadic space

A model of the functional release unit (FRU) in rat cardiac muscle consisti ng of one dihydropyridine receptor (DHPR) and eight ryanodine receptor (RyR ) channels, and the volume surrounding them, is formulated. It is assumed t hat no spatial [Ca2+] gradients exist in this volume, and that each FRU act s independently. The model is amenable to systematic parameter studies in w hich FRU dynamics are simulated at the channel level using Monte Carlo meth ods with Ca2+ concentrations simulated by numerical integration of a couple d system of differential equations. Using stochastic methods, Ca2+-induced Ca2+ release (CICR) shows both high gain and graded Ca2+ release that is ro bust when parameters are varied. For a single DHPR opening, the resulting R yR Ca2+ release flux is insensitive to the DHPR open duration, and is deter mined principally by local sarcoplasmic reticulum (SR) Ca2+ load, consisten t with experimental data on Ca2+ sparks. In addition, single RyR openings a re effective in triggering Ca2+ release from adjacent RyRs only when open d uration is long and SR Ca2+ load is high. This indicates relatively low cou pling between RyRs, and suggests a mechanism that limits the regenerative s pread of RyR openings. The results also suggest that adaptation plays an im portant modulatory role in shaping Ca2+ release duration and magnitude, but is not solely responsible for terminating Ca2+ release. Results obtained w ith the stochastic model suggest that high gain and gradedness can occur by the recruitment of independent FRUs without requiring spatial [Ca2+] gradi ents within a functional unit or cross-coupling between adjacent functional units.