IP₃R activity increases propensity of RyR-mediated sparks by elevating dyadic [Ca^2＋]

Calcium (Ca^2＋) plays a critical role in the excitation contraction coupling (ECC) process that mediates the contraction of cardiomyocytes during each heartbeat. While ryanodine receptors (RyRs) are the primary Ca^2＋ channels responsible for generating the cell-wide Ca^2＋ transients during ECC, Ca^2＋ release, via inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs) are also reported in cardiomyocytes to elicit ECC-modulating effects. Recent studies suggest that the localization of IP₃Rs at dyads grant their ability to modify the occurrence of Ca^2＋ sparks (elementary Ca^2＋ release events that constitute cell wide Ca^2＋ releases associated with ECC) which may underlie their modulatory influence on ECC. Here, we aim to uncover the mechanism by which dyad-localized IP₃Rs influence Ca^2＋ spark dynamics. To this end, we developed a mathematical model of the dyad that incorporates the behaviour of IP₃Rs, in addition to RyRs, to reveal the impact of their activity on local Ca^2＋ handling and consequent Ca^2＋ spark occurrence and its properties. Consistent with published experimental data, our model predicts that the propensity for Ca^2＋ spark formation increases in the presence of IP₃R activity. Our simulations support the hypothesis that IP₃Rs elevate Ca^2＋ in the dyad, sensitizing proximal RyRs towards activation and hence Ca^2＋ spark formation. The stochasticity of IP₃R gating is an important aspect of this mechanism. However, dyadic IP₃R activity lowers the Ca^2＋ available in the junctional sarcoplasmic reticulum (JSR) for release, thus resulting in Ca^2＋ sparks with similar durations but lower amplitudes.