Predicting local SR Ca(2+) dynamics during Ca(2+) wave propagation in ventricular myocytes

Abstract

Of the many ongoing controversies regarding the workings of the sarcoplasmic reticulum (SR) in cardiac myocytes, two unresolved and interconnected topics are 1), mechanisms of calcium (Ca(2+)) wave propagation, and 2), speed of Ca(2+) diffusion within the SR. Ca(2+) waves are initiated when a spontaneous local SR Ca(2+) release event triggers additional release from neighboring clusters of SR release channels (ryanodine receptors (RyRs)). A lack of consensus regarding the effective Ca(2+) diffusion constant in the SR (D(Ca,SR)) severely complicates our understanding of whether dynamic local changes in SR [Ca(2+)] can influence wave propagation. To address this problem, we have implemented a computational model of cytosolic and SR [Ca(2+)] during Ca(2+) waves. Simulations have investigated how dynamic local changes in SR [Ca(2+)] are influenced by 1), D(Ca,SR); 2), the distance between RyR clusters; 3), partial inhibition or stimulation of SR Ca(2+) pumps; 4), SR Ca(2+) pump dependence on cytosolic [Ca(2+)]; and 5), the rate of transfer between network and junctional SR. Of these factors, D(Ca,SR) is the primary determinant of how release from one RyR cluster alters SR [Ca(2+)] in nearby regions. Specifically, our results show that local increases in SR [Ca(2+)] ahead of the wave can potentially facilitate Ca(2+) wave propagation, but only if SR diffusion is relatively slow. These simulations help to delineate what changes in [Ca(2+)] are possible during SR Ca(2+)release, and they broaden our understanding of the regulatory role played by dynamic changes in [Ca(2+)](SR).