Protein geometry and placement in the cardiac dyad influence macroscopic properties of calcium-induced calcium release

In cardiac ventricular myocytes, events crucial to excitation- contraction coupling take place in spatially restricted microdomains known as dyads. The movement and dynamics of calcium ( Ca2+) ions in the dyad have often been described by assigning continuously valued Ca2+ concentrations to one or more dyadic compartments. However, even at its peak, the estimated number of free Ca2+ ions present in a single dyad is small (similar to 10 - 100 ions). This in turn suggests that modeling dyadic calcium dynamics using laws of mass action may be inappropriate. In this study, we develop a model of stochastic molecular signaling between L- type Ca2+ channels ( LCCs) and ryanodine receptors ( RyR2s) that describes: a), known features of dyad geometry, including the space-filling properties of key dyadic proteins; and b), movement of individual Ca2+ ions within the dyad, as driven by electrodiffusion. The model enables investigation of how local Ca2+ signaling is influenced by dyad structure, including the configuration of key proteins within the dyad, the location of Ca2+ binding sites, and membrane surface charges. Using this model, we demonstrate that LCC- RyR2 signaling is in. uenced by both the stochastic dynamics of Ca2+ ions in the dyad as well as the shape and relative positioning of dyad proteins. Results suggest the hypothesis that the relative placement and shape of the RyR2 proteins helps to funnel'' Ca2+ ions to RyR2 binding sites, thus increasing excitation- contraction coupling gain.