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A 3D Monte Carlo Analysis of the Role of Dyadic Space Geometry in Spark Generation

Whitaker Institute for Biomedical Engineering and Department of Biomedical Engineering, The Johns Hopkins University Whiting School of Engineering, Baltimore, Maryland

Correspondence: Address reprint requests to Andre Levchenko, Whitaker Institute for Biomedical Engineering, Dept. of Biomedical Engineering, The Johns Hopkins University Whiting School of Engineering, 208C Clark Hall, 3400 North Charles St., Baltimore, MD 21218. Tel.: 410-516-5584; Fax: 410-516-6240; E-mail: alev{at}jhu.edu.

In multiple biological systems, vital intracellular signaling processes occur locally in minute periplasmic subspaces often referred to as signaling microdomains. The number of signaling molecules in these microdomains is small enough to render the notion of continuous concentration changes invalid, such that signaling events are better described using stochastic rather than deterministic methods. Of particular interest is the dyadic cleft in the cardiac myocyte, where short-lived, local increases in intracellular Ca²⁺ known as Ca²⁺ sparks regulate excitation-contraction coupling. The geometry of dyadic spaces can alter in disease and development and display significant interspecies variability. We created and studied a 3D Monte Carlo model of the dyadic cleft, specifying the spatial localization of L-type Ca²⁺ channels and ryanodine receptors. Our analysis revealed how reaction specificity and efficiency are regulated by microdomain geometry as well as the physical separation of signaling molecules into functional complexes. The spark amplitude and rise time were found to be highly dependent on the concentration of activated channels per dyadic cleft and on the intermembrane separation, but not very sensitive to other cleft dimensions. The role of L-type Ca²⁺ channel and ryanodine receptor phosphorylation was also examined. We anticipate that this modeling approach may be applied to other systems (e.g., neuronal growth cones and chemotactic cells) to create a general description of stochastic events in Ca²⁺ signaling.

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