Simulations of Subcellular Heterogeneity in Calcium Blink Kinetics

Abstract

In cardiac myocytes, calcium (Ca2+) release from the sarcoplasmic reticulum (SR) depends on local calcium concentrations in both the cytosol and the SR. The local dynamics of SR Ca2+ depletion have been visualized experimentally through the recording of Ca2+ “blinks.” Specifically, it has been shown that blink nadir is relatively reproducible between local Ca2+ release sites whereas blink recovery kinetics are highly variable. We applied a spatially-detailed, stochastic mathematical model to gain insight into the mechanisms underlying this heterogeneity.Novel features of our model include: (1) calculation of Ca2+ fluxes between locations within the junctional SR (JSR) and dyadic spaces; (2) variable numbers and locations of connections between the JSR and the SR network; (3) variable and irregular clusters of ryanodine receptor (RyR) channels in the JSR membrane; (4) spatially-defined localization of SR Ca2+ pumps (SERCA) in JSR and network SR membranes. Using this model, we investigated how different parameters influenced Ca2+ blink amplitude and kinetics. From these simulations we determined that the number of connections between the JSR and the SR network was the most important parameter controlling Ca2+ blink recovery kinetics. For instance, 80% recovery of pre-release JSR [Ca2+] decreased from 400 ms with 1 connection to 125 ms with 5 connections.SERCA density also influenced Ca2+ blink recovery, but the quantitative strength of this effect was relatively smaller (126 ms at nominal SERCA versus 209 ms with SERCA reduced by 80%). The remaining model parameters had only minor effects on blink kinetics. These results indicate the importance of SR Ca2+ diffusion in release kinetics and suggest mechanisms underlying Ca2+ blink heterogeneity.