Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum.
The t-tubules 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 (Ca(2+)). To investigate how the t-tubule microanatomy and the distribution of membrane Ca(2+) flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca(2+) 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 Ca(2+) signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca(2+) flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca(2+) buffers, including the Ca(2+) 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 Ca(2+) transients was found when the Ca(2+) flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca(2+) signals are predicted. Even at modest elevation of Ca(2+), reached during Ca(2+) influx, large and steep Ca(2+) gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca(2+) flux density along the cell membrane support initiation and propagation of Ca(2+) waves in rat myocytes.
Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.
Yuhui
Y
Cheng
Zeyun
Z
Yu
Masahiko
M
Hoshijima
Michael J
MJ
Holst
Andrew D
AD
McCulloch
J Andrew
JA
McCammon
Anushka P
AP
Michailova
D000255:Adenosine Triphosphate / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D021621:Imaging, Three-Dimensional; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D012984:Software
D002147:Calmodulin; D000255:Adenosine Triphosphate