Key result
In silico simulations of cardiac calcium release sites demonstrated that calcium release event characteristics follow the law of mass action with respect to a state variable defined by RyR vicinity and single-channel calcium current.
Why the study?
It remained unclear how geometric factors of variable RyR channel clustering in cardiac dyads translate into the formation of calcium release events.
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This in silico study demonstrates that the spatial distribution of ryanodine receptors and single-channel calcium current synergistically determine the characteristics of calcium release events in cardiac dyads.
Recent data on structure of dyads in cardiac myocytes indicate variable clustering of RyR calcium release channels. The question arises as to how geometric factors of RyR arrangement translate to their role in formation of calcium release events (CRE). Since this question is not experimentally testable in situ , we performed in silico experiments on a large set of calcium release site (CRS) models. The models covered the range of RyR spatial distributions observed in dyads, and included gating of RyRs with open probability dependent on Ca 2+ and Mg 2+ concentration. The RyR single-channel calcium current, varied in the range of previously reported values, was set constant in the course of CRE simulations. Other known features of dyads were omitted in the model formulation for clarity. CRE simulations initiated by a single random opening of one of the RyRs in a CRS produced spark-like responses with characteristics that varied with RyR vicinity, a newly defined parameter quantifying spatial distribution of RyRs in the CRSs, and with the RyR single-channel calcium current. The CRE characteristics followed the law of mass action with respect to a CRS state variable, defined as a weighed product of RyR vicinity and RyR single-channel calcium current. The results explained the structure-function relations among determinants of cardiac dyads on synergy principles and thus allowed to evolve the concept of CRS as a dynamic unit of cardiac dyad.
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Iaparov et al. (2020) studied Calcium release events in cardiac myocytes. In silico calcium release site (CRS) models was evaluated on Characteristics of calcium release events (quarks, blips, sparks). In silico simulations of cardiac calcium release sites demonstrated that calcium release event characteristics follow the law of mass action with respect to a state variable defined by RyR vicinity and single-channel calcium current.
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