Modeling the Crosstalk between Ryanodine and IP3 Receptors in Cardiac Myocytes

Abstract

Ryanodine receptors (RYR) and IP3 receptors (IP3R) are calcium channels expressed on the endoplasmic/sarcoplasmic reticulum (ER/SR) membrane in various cell types. Both the spatial localization and the distinct gating properties of these channels contribute to the diverse cellular functions controlled by intracellular calcium signaling. It is known that both RYRs and IP3Rs are expressed on the SR membrane of cardiac myocytes and that the expression of IP3Rs on the SR at dyadic junctions is increased in cardiac disease, and evidence that calcium release through IP3Rs can influence RyR-mediate calcium release has been described. However, despite the suggested functional role for crosstalk between RYRs and IP3Rs, especially in cardiac disease, most previous mathematical models of myocyte calcium signaling have accounted for only RYRs in isolation. Here, we propose a mathematical model of intracellular calcium signaling that incorporates both RYRs and IP3Rs and can be used to develop quantitative predictions of crosstalk between the two channels. This model considers the spatial arrangement of RYRs and IP3Rs relative to one another based on published co-localization studies using immunohistochemistry and simulates the stochastic opening and closing of individual receptors based on previously published models of calcium sparks and puffs. In these models, gating of RYRs depends on the local cytosolic and JSR calcium concentration as well as the number of neighboring RYRs that are open while IP3R gating depends primarily on local cytosolic calcium and IP3 concentrations. Based on preliminary results, we hypothesize that the subcellular spatial remodeling and increased expression of IP3Rs that occurs in cardiac disease will increase the probability of diastolic calcium spark events, which may contribute to the increased risk of arrhythmia in those with cardiac diseases such as hypertrophy and heart failure.