Biophys J, October 1999, p. 1871-1884, Vol. 77, No. 4

Modeling Gain and Gradedness of Ca²⁺ Release in the Functional Unit of the Cardiac Diadic Space

Department of Biomedical Engineering and Center for Computational Medicine and Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 USA

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 [Ca²⁺] 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 Ca²⁺ concentrations simulated by numerical integration of a coupled system of differential equations. Using stochastic methods, Ca²⁺-induced Ca²⁺ release (CICR) shows both high gain and graded Ca²⁺ release that is robust when parameters are varied. For a single DHPR opening, the resulting RyR Ca²⁺ release flux is insensitive to the DHPR open duration, and is determined principally by local sarcoplasmic reticulum (SR) Ca²⁺ load, consistent with experimental data on Ca²⁺ sparks. In addition, single RyR openings are effective in triggering Ca²⁺ release from adjacent RyRs only when open duration is long and SR Ca²⁺ 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 Ca²⁺ release duration and magnitude, but is not solely responsible for terminating Ca²⁺ release. Results obtained with the stochastic model suggest that high gain and gradedness can occur by the recruitment of independent FRUs without requiring spatial [Ca²⁺] gradients within a functional unit or cross-coupling between adjacent functional units.

Biophys J, October 1999, p. 1871-1884, Vol. 77, No. 4
© 1999 by the Biophysical Society   0006-3495/99/10/1871/14  $2.00

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