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

DeAnalisa C. JonesEric A Sobie^*

• Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States

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. Both RyR2s and IP3R2s are expressed on the SR membrane of ventricular cardiomyocytes, and the expression of IP3R2s is increased in cardiac diseases such as heart failure (HF). However, despite a 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 RyR2 clusters 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. 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. In remodeled RyR2 clusters observed in HF, Ca2+ spark probability increases with increasing IP3R2 expression. Furthermore, IP3R2 expression mitigates differences in total Ca2+ released during a Ca2+ spark and spark duration observed when fragmentation and dispersion of RyR2 clusters alone was simulated. This mathematical modeling study suggests IP3R2 expression in the context of HF (1) contributes to pro-arrhythmic Ca2+ signaling as increased Ca2+ spark frequency and (2) may serve a compensatory function by undoing changes in Ca2+ spark morphology that arise due to RyR2 cluster remodeling.