A 3D Monte Carlo analysis of the role of dyadic space geometry in spark generation

¹ Massachusetts Institute of Technology, Biological Engineering Division
² Whitaker Biomedical Engineering Institute, Johns Hopkins University

^* To whom correspondence should be addressed. E-mail: alev{at}jhu.edu.

Submitted on May 3, 2005
Revised on July 20, 2005
Accepted on 5 December 2005

	Abstract

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 inter-species 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.

Key Words: LCC, RyR, calcium, dyadic cleft, stochastic

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