Seminar Abstract

“Exploring Ca2+ release mechanisms in cardiac cells”

Ca2+-induced Ca2+ release (CICR) is widely accepted as the principal mechanism linking between electrical excitation and mechanical contraction in cardiac cells. However, Ca2+ release mechanisms that determine the fraction of sarcoplasmic reticulum (SR) Ca2+ release are not well understood. Using mathematical models we explored two possible mechanisms that may lead to nonlinear fractional SR Ca2+ release. First, a mathematical model, based on the one-dimensional reaction-diffusion model of Keizer-Smith 1998, showed that alternating patterns of Ca2+ wave propagation can occur with periodic Ca2+ stimulation under conditions of Ca2+ overload. From this model we speculate that such behavior results from a delay in recovery from refractoriness of RyR channel kinetics. Second, we developed a kinetic model of RyR that has three binding sites, two cytosolic sites for Ca2+ activation and inactivation, and one SR luminal site for calsequestrin (CSQ) binding. The RyR kinetic model was incorporated into a local CICR model that has both a diadic space and junctional SR (jSR). This model suggests that CSQ has an inhibitory effect on RyR gating at low jSR load as more CSQs bind to RyR. This local CICR model also produces a nonlinear fractional relation of jSR Ca2+ release on jSR load. These putative Ca2+ release mechanisms currently are being investigated experimentally in canine cardiac Purkinje cells.