IP3R activity increases frequency of RyR-mediated sparks by elevating dyadic Ca2+

Abstract

Calcium (Ca2+) 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 Ca2+ channels responsible for mediating cell-wide Ca2+ transients during ECC, Ca2+ release via inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) have been reported to elicit ECC-modulating effects. Recent studies suggest that the proximal localization of IP3Rs at dyads grants their ability to modify the occurrence of Ca2+ sparks (elementary Ca2+ release events that constitute ECC-associated Ca2+ transients) which may underlie the modulatory effects on ECC. Here, we aim to uncover the mechanism by which IP3Rs affect Ca2+ spark dynamics. To this end, we developed a mathematical model of the dyad that incorporates IP3Rs to reveal their impact on local Ca2+ handling and corresponding Ca2+ spark formation. Consistent with published experimental data, our model predicts that the propensity for Ca2+ spark formation increases with IP3R activity. Our simulations support the hypothesis that IP3R activity elevates Ca2+ within the dyad, sensitizing proximal RyRs for future release. However, this lowers Ca2+ in the JSR available for release and thus results in Ca2+ sparks with the same duration but lower amplitudes.