AbstractCalcium 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 (IP3Rs) is also reported in cardiomyocytes. IP3R calcium release modifies ECC as well as contributing to downstream regulation of hypertrophic gene expression. Recent studies suggest that proximal localisation of IP3Rs with RyRs contributes to their ability to modify Ca2+ handling during ECC. Here we aim to determine the mechanism by which IP3Rs modify Ca2+ 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 IP3Rs on spark activation. By testing multiple spark initiation mechanisms, we find that Ca2+ release via IP3Rs result in increased propensity for spark initiation within the cardiac dyad. Our simulations suggest that opening of IP3Rs elevates Ca2+ within the dyad, which increase the probability of spark initiation. Finally, we find that while increasing the number of IP3Rs increases the probability of spark formation, it has little effect on spark amplitude, duration, or overall shape. Our study therefore suggests that IP3R play a critical role in modulating Ca2+ signaling for excitation contraction couplingAuthor summaryWhile Ca2+ release through ryanodine receptors (RyRs) initiates contraction in cardiomyocytes, the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in cardiomyocytes is less clear with Ca2+ release through these channels being invoked in regulating ECC and hypertrophic signalling. RyRs generate cytosolic Ca2+ signals through elemental Ca2+ release events called sparks. The mechanisms by which IP3Rs influence cytosolic Ca2+ are not well understood. We created a 1D model of calcium spark formation in a cardiomyocyte dyad—the primary site of elemental RyR-based calcium release. We investigated possible behaviours of IP3Rs and their interaction with RyRs in generating Ca2+ sparks. We show that for high IP3 concentration, a large number of IP3Rs and high IP3R affinity are required to noticeably affect spark shape. At lower IP3 concentration IP3Rs can increase Ca2+ spark activity, but do not significantly alter the spark shape. Finally our simulations suggest that spark frequency can be reliably increased when IP3Rs activity is such that a small continuous Ca2+ flux is introduced to the dyad to elevate Ca2+, and not via brief but high Ca2+ release from these receptors.
Postnatal maturation of excitation-contraction coupling in rat ventricle in relation to the subcellular localization and surface density of 1,4-dihydropyridine and ryanodine receptors.
