Modeling the spatiotemporal properties of crosstalk between RYR and IP3R-mediated Ca2+release in failing cardiomyocytes.

Abstract

Ryanodine receptors (RyR) and IP3 receptors (IP3R) are Ca2+ 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 Ca2+ signaling. It is known that both RyRs and IP3Rs are expressed on the SR membrane of ventricular cardiomyocytes and that the expression of IP3Rs on the SR at dyadic junctions is increased in cardiac diseases such as hypertrophy and heart failure (HF), and evidence that Ca2+ release through IP3Rs can influence RyR-mediated Ca2+ release has been described. However, despite the suggested functional role for crosstalk between RyRs and IP3Rs, especially under pathological conditions, most previous mathematical models of cardiomyocyte Ca2+ signaling have accounted for only RyRs in isolation. Here, we propose a mathematical model of intracellular Ca2+ signaling that incorporates both RyRs and IP3Rs and can be used to develop quantitative predictions about crosstalk between the two channels. This model considers the spatial arrangement of RyRs and IP3Rs relative to one another based on published immunohistochemistry co-localization studies and simulates the stochastic opening and closing of individual receptors based on previously published models of Ca2+ sparks and puffs. In this model, RyR gating depends on local cytosolic [Ca2+], JSR [Ca2+], and allosteric coupling to neighboring RyRs while IP3R gating depends primarily on local cytosolic [Ca2+] and [IP3]. Based on preliminary results, we hypothesize that the subcellular spatial remodeling and increased expression of IP3Rs that occur in hypertrophy and HF will promote slowed, uncoordinated diastolic Ca2+ sparks, which may contribute to increased risk of arrhythmogenic Ca2+ wave formation and incidence of ventricular arrhythmias observed clinically in patients with hypertrophy and HF.