IP ₃ R activity increases frequency of RyR-mediated sparks by elevating dyadic Ca ²⁺

Calcium (Ca 2+ ) plays a critical role in the excitation contraction coupling (ECC) process that governs the contraction of cardiomyocytes during each heartbeat. While ryanodine receptors (RyRs) are the primary Ca 2+ channels responsible for mediating cell-wide Ca 2+ transients during ECC, Ca 2+ release via inositol 1,4,5-trisphosphate (IP 3 ) receptors (IP 3 Rs) have been reported to elicit ECC-modulating effects. Recent studies suggest that the proximal localization of IP 3 Rs at dyads grants their ability to modify the occurrence of Ca 2+ sparks (elementary Ca 2+ release events that constitute ECC-associated Ca 2+ transients) which may underlie the modulatory effects on ECC. Here, we aim to uncover the mechanism by which IP 3 Rs affect Ca 2+ spark dynamics. To this end, we developed a mathematical model of the dyad that incorporates IP 3 Rs to reveal their impact on local Ca 2+ handling and corresponding Ca 2+ spark formation. Consistent with published experimental data, our model predicts that the propensity for Ca 2+ spark formation increases with IP 3 R activity. Our simulations support the hypothesis that IP 3 R activity elevates Ca 2+ within the dyad, sensitizing proximal RyRs for future release. However, this lowers Ca 2+ in the JSR available for release and thus results in Ca 2+ sparks with the same duration but lower amplitudes.