IPR activity increases propensity of RyR-mediated sparks by elevating dyadic [Ca].

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