Numerical Analysis of Ca2+ Signaling in Rat Ventricular Myocytes with Realistic Transverse-Axial Tubular Geometry and Inhibited Sarcoplasmic Reticulum.

The t-tubule's of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca²⁺). To investigate how the t-tubulemicroanatomy and the distribution of membrane Ca²⁺ flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca²⁺ signaling, buffering and diffusion in rat ventricular myocytes. The transverse-axial t-tubule geometry was derived from light microscopy structural data. To solve the nonlinear reaction-diffusion system we extended SMOL software tool (http://mccammon.ucsd.edu/smol/). The analysis suggests that the quantitative understanding of the Ca²⁺ signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca2+ flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca²⁺ buffers, including the Ca²⁺ indicator dye. In agreement with experiment, in the presence of fluorescence dye and inhibited sarcoplasmic reticulum, the lack of detectible differences in the depolarization-evoked Ca²⁺ transients was found when the Ca²⁺ flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca²⁺ signals are predicted. Even at modest elevation of Ca²⁺, reached during Ca²⁺ influx, large and steep Ca²⁺ gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca²⁺ flux density along the cell membrane support initiation and propagation of Ca²⁺ waves in rat myocytes. [ABSTRACT FROM AUTHOR]