Ca 2+ release via IP 3 Rs increases RyR mediated Ca 2+ spark frequency in ventricular cardiomyocytes without altering spark amplitude and duration

Calcium plays critical roles in cardiac cells, coupling electrical excitation to mechanical contraction with each heartbeat, while simultaneously mediating biochemical signals that regulate cell growth. While ryanodine receptors (RyRs) are fundamental to generation of elementary calcium release events (sparks) and global calcium elevations that underlie excitation-contraction coupling (ECC), calcium release via inositol 1,4,5-trisphosphate receptors (IPRs) is also reported in cardiomyocytes. IPR calcium release modifies ECC as well as contributing to downstream regulation of hypertrophic gene expression. Recent studies suggest that proximal localisation of IPRs with RyRs contributes to their ability to modify Ca handling during ECC. Here we aim to determine the mechanism by which IPRs modify Ca handling in cardiomyocytes. We develop a mathematical model incorporating the stochastic behaviour of receptor opening that allows for the parametric tuning of the system to reveal the impact of IPRs on spark activation. By testing multiple spark initiation mechanisms, we find that Ca release via IPRs result in increased propensity for spark initiation within the cardiac dyad. Our simulations suggest that opening of IPRs elevates Ca within the dyad, which increase the probability of spark initiation. Finally, we find that while increasing the number of IPRs increases the probability of spark formation, it has little effect on spark amplitude, duration, or overall shape. Our study therefore suggests that IPR play a critical role in modulating Ca signaling for excitation contraction coupling