Modeling Ca2+ Induced Ca2+ Release Between Neighboring Ryanodine Receptors

Abstract

In the heart, Ca2+ is released from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyR). A small Ca2+ trigger activates a RyR, which then mediates a larger Ca2+ flux sufficient to activate neighboring RyRs. The inherent positive feedback of Ca2+ induced Ca2+ release (CICR) should cause Ca2+ release to continue until the SR is empty. This phenomenon does not occur in cells. In order to understand why, we have developed a simple physical model to describe CICR using simulations of discrete RyR channels on a two dimensional grid. RyR open probability (Po) is defined through a traditional two-site Hill function comprised of one cytosolic Ca2+ activation and one cytosolic Ca2+ inactivation sites per subunit. The diffusion equation for a steady state point source of Ca2+ current defines the Ca2+ concentration everywhere in the system. Single channel experimental Ca2+ dissociation constant values were used. Our Metropolis Monte Carlo simulations quantitatively reproduce Po's measured as a function of cytosolic Ca2+ for both single RyR as well as a two-RyR channel system reconstituted in bilayers. Our simulations suggest a mechanism for CICR termination requiring only a reduction in unitary Ca2+ current. Small changes in Ca2+ current produce large and sudden changes in overall activity in RyR arrays. Our simulations show reducing current may terminate release well before depletion of the SR at Ca2+ loads consistent with experiment. This current-termination occurs independently from any form of luminal regulation or coupled gating. Thus, we propose CICR termination may be due to a drop in single channel Ca2+ current as local intra-SR Ca2+ levels fall during release.