Protein geometry and placement in the cardiac dyad influence macroscopic
properties of calcium-induced calcium release.
Biophys. J., 92 (10):
3379--3396 (May 2007)DOI: 10.1529/biophysj.106.089425
Abstract
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 (Ca$^2+$) ions in
the dyad have often been described by assigning continuously valued
Ca$^2+$ concentrations to one or more dyadic compartments. However,
even at its peak, the estimated number of free Ca$^2+$ ions present
in a single dyad is small (approximately 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 Ca$^2+$ 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 Ca$^2+$
ions within the dyad, as driven by electrodiffusion. The model enables
investigation of how local Ca$^2+$ signaling is influenced by
dyad structure, including the configuration of key proteins within
the dyad, the location of Ca$^2+$ binding sites, and membrane
surface charges. Using this model, we demonstrate that LCC-RyR2 signaling
is influenced by both the stochastic dynamics of Ca$^2+$ 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" Ca$^2+$ ions
to RyR2 binding sites, thus increasing excitation-contraction coupling
gain.
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