Protein Geometry and Placement in the Cardiac Dyad Influence Macroscopic Properties of Calcium-Induced Calcium-Release

¹ The Johns Hopkins University
² The Johns Hopkins University, Institute for Computational Medicine

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

Submitted on May 18, 2006
Revised on July 2, 2006
Accepted on 9 January 2007

	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 (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 (~ 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 electro-diffusion. 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 influenced 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.

Key Words: L-type calcium channel, calcium-induced calcium release, cardiac dyad, cardiac myocyte, ryanodine receptor, stochastic simulation

This article has been cited by other articles:

				J. Hake and G. T. Lines Stochastic Binding of Ca2+ Ions in the Dyadic Cleft; Continuous versus Random Walk Description of Diffusion Biophys. J., June 1, 2008; 94(11): 4184 - 4201. [Abstract] [Full Text] [PDF]