Formation and Regulation of Calcium Sparks on a Nonlinear Spatial Network of Ryanodine Receptors

Abstract: Accurate regulation of calcium release is essential for cellular signaling, with the spatial distribution of ryanodine receptors (RyRs) playing a critical role. In this study, we present a nonlinear spatial network model that simulates RyR spatial organization to investigate calcium release dynamics by integrating RyR behavior, calcium buffering, and calsequestrin (CSQ) regulation. The model successfully reproduces calcium sparks, shedding light on their initiation, duration, and termination mechanisms under clamped calcium conditions. Our simulations demonstrate that RyR clusters act as on-off switches for calcium release, producing short-lived calcium quarks and longer-lasting calcium sparks based on distinct activation patterns. Spark termination is governed by calcium gradients and stochastic RyR dynamics, with CSQ facilitating RyR closure and spark termination. We also uncover the dual role of CSQ as both a calcium buffer and a regulator of RyRs. Elevated CSQ levels prolong calcium release due to buffering effects, while CSQ-RyR interactions induce excessive refractoriness, a phenomenon linked to pathological conditions such as ventricular arrhythmias. Dysregulated CSQ function disrupts the on-off switching behavior of RyRs, impairing calcium release dynamics. These findings provide new insights into RyR-mediated calcium signaling, highlighting CSQ's pivotal role in maintaining calcium homeostasis and its implications for pathological conditions. This work advances the understanding of calcium spark regulation and underscores its significance for cardiomyocyte function.