Modeling the spatiotemporal properties of crosstalk between RyR-mediated and IP₃R-mediated local Ca²⁺ release

Ryanodine receptors (RyR) and IP₃ receptors (IP₃R) are Ca²⁺ release 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 RyR2s and IP₃R2s are expressed on the SR membrane of ventricular cardiomyocytes and that the expression of IP₃R2s on the SR is increased in cardiac diseases such as heart failure (HF), and evidence that Ca²⁺ release through IP₃R2s can influence RyR2-mediated Ca²⁺ release in excitation-contraction coupling has been described. However, despite the suggested functional role for crosstalk between RyR2s and IP₃R2s, especially under pathologic conditions, most previous mathematical models of cardiomyocyte Ca²⁺ signaling have accounted for only RyR2s in isolation. We hypothesized that the combined effects of (1) fragmentation and dispersion of RyR2s within calcium release units (CRUs) and (2) increased expression of IP₃R2s that occur in HF promote pro-arrhythmic Ca²⁺ spark behavior, which may contribute to increased risk of arrhythmogenic Ca²⁺ wave formation and incidence of ventricular arrhythmias. We built a stochastic mathematical model of local SR Ca²⁺ release events-Ca²⁺ sparks-that incorporates both RyR2s and IP₃R2s. This model considers the spatial arrangement of RyR2s and IP₃R2s relative to one another based on published immunohistochemistry studies and the arrangement of RyR2s under HF and healthy control conditions based on super-resolution microscopy data. RyR2 and IP₃R2 gating are modeled based on single channel patch clamp studies which show that (1) RyR2 gating is stochastic and depends on local cytosolic [Ca²⁺], JSR [Ca²⁺], and allosteric coupling, (2) IP₃R2 gating is stochastic and depends primarily on local cytosolic [Ca²⁺] and [IP₃], and the (3) RyR2 has a larger single channel Ca²⁺ current than the IP₃R2. Our simulations show that Ca²⁺ spark probability increases with increasing IP₃R2 expression in HF CRUs and IP₃R2 expression mitigates differences in mean duration of and mean total Ca²⁺ released during Ca²⁺ sparks observed in simulations in which HF is modeled as fragmentation and dispersion of RyR2s within CRUs alone. Overall, this mathematical modeling study suggests that increased IP₃R2 expression in the context of HF may contribute to pro-arrhythmic Ca²⁺ signaling via increased Ca²⁺ spark frequency but may also serve a compensatory function by countering changes in Ca²⁺ spark morphology that arise due to RyR2 remodeling within CRUs in HF.