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Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum.

Cheng Y, Yu Z, Hoshijima M, Holst MJ, McCulloch AD, McCammon JA, Michailova AP - PLoS Comput. Biol. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
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.

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Model predictions in the absence of Fluo-3 and Ca2+ pathways heterogeneously distributed via the cell membrane.(A–B) The voltage-clamp protocol and whole-cell L-type Ca2+ current used in this set of simulations. (C–D) The predicted global Na+/Ca2+ and Ca2+ leak currents. (E–F) The global Ca2+ transient and Ca2+ concentrations visualized as line-scan image in the transverse cell direction. (G) Local Ca2+ transients taken at three featured spots along the scanning line (0.17 µm – blue lines, 3.09 µm – green lines, 5.45 µm – red lines). In (H–I) the spatial profile of Ca2+ along the scanning line and 3-D [Ca2+]i distribution at Ca2+ peak of 76 ms are shown. In this numerical experiment the scanned line was positioned at 200nm away from the t-tubule membrane at the angle 120°.
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pcbi-1000972-g006: Model predictions in the absence of Fluo-3 and Ca2+ pathways heterogeneously distributed via the cell membrane.(A–B) The voltage-clamp protocol and whole-cell L-type Ca2+ current used in this set of simulations. (C–D) The predicted global Na+/Ca2+ and Ca2+ leak currents. (E–F) The global Ca2+ transient and Ca2+ concentrations visualized as line-scan image in the transverse cell direction. (G) Local Ca2+ transients taken at three featured spots along the scanning line (0.17 µm – blue lines, 3.09 µm – green lines, 5.45 µm – red lines). In (H–I) the spatial profile of Ca2+ along the scanning line and 3-D [Ca2+]i distribution at Ca2+ peak of 76 ms are shown. In this numerical experiment the scanned line was positioned at 200nm away from the t-tubule membrane at the angle 120°.

Mentions: This model is also able to predict the spatial [Ca2+]i signals that would occur in the absence of Fluo-3 (note experiments without fluorescent dye cannot be performed because of technical reasons). Since it has been suggested that the dye could not affect Ca2+ entry via L-type channels [63], [64], the same global LCC flux (as in Figs. 4–5) was used during this numerical experiment. Figures 6E–I show predicted Ca2+ signals arising from the ionic influx via L-type Ca2+ channels during voltage-clamp stimulation with LCC and NCX pathways heterogeneously distributed (as in Fig. 4F). The calculated global NCX and Ca2+ leak currents are shown in Figs. 6C–D, respectively.


Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum.

Cheng Y, Yu Z, Hoshijima M, Holst MJ, McCulloch AD, McCammon JA, Michailova AP - PLoS Comput. Biol. (2010)

Model predictions in the absence of Fluo-3 and Ca2+ pathways heterogeneously distributed via the cell membrane.(A–B) The voltage-clamp protocol and whole-cell L-type Ca2+ current used in this set of simulations. (C–D) The predicted global Na+/Ca2+ and Ca2+ leak currents. (E–F) The global Ca2+ transient and Ca2+ concentrations visualized as line-scan image in the transverse cell direction. (G) Local Ca2+ transients taken at three featured spots along the scanning line (0.17 µm – blue lines, 3.09 µm – green lines, 5.45 µm – red lines). In (H–I) the spatial profile of Ca2+ along the scanning line and 3-D [Ca2+]i distribution at Ca2+ peak of 76 ms are shown. In this numerical experiment the scanned line was positioned at 200nm away from the t-tubule membrane at the angle 120°.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2965743&req=5

pcbi-1000972-g006: Model predictions in the absence of Fluo-3 and Ca2+ pathways heterogeneously distributed via the cell membrane.(A–B) The voltage-clamp protocol and whole-cell L-type Ca2+ current used in this set of simulations. (C–D) The predicted global Na+/Ca2+ and Ca2+ leak currents. (E–F) The global Ca2+ transient and Ca2+ concentrations visualized as line-scan image in the transverse cell direction. (G) Local Ca2+ transients taken at three featured spots along the scanning line (0.17 µm – blue lines, 3.09 µm – green lines, 5.45 µm – red lines). In (H–I) the spatial profile of Ca2+ along the scanning line and 3-D [Ca2+]i distribution at Ca2+ peak of 76 ms are shown. In this numerical experiment the scanned line was positioned at 200nm away from the t-tubule membrane at the angle 120°.
Mentions: This model is also able to predict the spatial [Ca2+]i signals that would occur in the absence of Fluo-3 (note experiments without fluorescent dye cannot be performed because of technical reasons). Since it has been suggested that the dye could not affect Ca2+ entry via L-type channels [63], [64], the same global LCC flux (as in Figs. 4–5) was used during this numerical experiment. Figures 6E–I show predicted Ca2+ signals arising from the ionic influx via L-type Ca2+ channels during voltage-clamp stimulation with LCC and NCX pathways heterogeneously distributed (as in Fig. 4F). The calculated global NCX and Ca2+ leak currents are shown in Figs. 6C–D, respectively.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus