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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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Calcium signals arising from the ionic fluxes via the external and t-tubule membrane in the presence of 100 µM Fluo-3.(A–B) The voltage-clamp protocol and whole-cell L-type Ca2+ current. (C–E) Predicted global Na+/Ca2+ and Ca2+ leak currents and global Ca2+ transient when no detectible differences in [Ca2+]i are found (see panel F). (F–H) Calcium concentrations visualized as line-scan images in transverse cell direction. (I–K) Local Ca2+ transients taken at three featured spots along the scanning line of interest: 0.17 µm – blue lines; 3.09 µm – green lines; 5.45 µm – red lines. In (F) and (I) the L-type Ca2+ current density followed heterogeneous distribution along the length of t-tubule as shown in Fig. 2A. In (G) and (J) the L-type Ca2+ current density was uniform along the t-tubule and six times higher than in external membrane. In (H) and (K) the L-type Ca2+ current density was homogeneous throughout the cell surface. In (F–G) Na+/Ca2+ flux density was three times higher in the t-tubule and Ca2+ leak homogeneously distributed. In (H) Na+/Ca2+ exchanger and Ca2+ leak were homogeneously distributed via the sarcolemma. (L) Local Ca2+ time-courses with re-plot from experimental data [5]. The re-plots were taken along the scanned line at 0µm (blue), 3.96 µm (green) and 5.65 µm (red) from the near surface location. (M) Estimated SCH values with respect to the three flux distribution choices. In this numerical experiment the line-scan was positioned at 200nm away from the t-tubule membrane at the angle 120°. The scanned line in Cheng et al. experiment was located at 200nm from the surface of the t-tubule.
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pcbi-1000972-g004: Calcium signals arising from the ionic fluxes via the external and t-tubule membrane in the presence of 100 µM Fluo-3.(A–B) The voltage-clamp protocol and whole-cell L-type Ca2+ current. (C–E) Predicted global Na+/Ca2+ and Ca2+ leak currents and global Ca2+ transient when no detectible differences in [Ca2+]i are found (see panel F). (F–H) Calcium concentrations visualized as line-scan images in transverse cell direction. (I–K) Local Ca2+ transients taken at three featured spots along the scanning line of interest: 0.17 µm – blue lines; 3.09 µm – green lines; 5.45 µm – red lines. In (F) and (I) the L-type Ca2+ current density followed heterogeneous distribution along the length of t-tubule as shown in Fig. 2A. In (G) and (J) the L-type Ca2+ current density was uniform along the t-tubule and six times higher than in external membrane. In (H) and (K) the L-type Ca2+ current density was homogeneous throughout the cell surface. In (F–G) Na+/Ca2+ flux density was three times higher in the t-tubule and Ca2+ leak homogeneously distributed. In (H) Na+/Ca2+ exchanger and Ca2+ leak were homogeneously distributed via the sarcolemma. (L) Local Ca2+ time-courses with re-plot from experimental data [5]. The re-plots were taken along the scanned line at 0µm (blue), 3.96 µm (green) and 5.65 µm (red) from the near surface location. (M) Estimated SCH values with respect to the three flux distribution choices. In this numerical experiment the line-scan was positioned at 200nm away from the t-tubule membrane at the angle 120°. The scanned line in Cheng et al. experiment was located at 200nm from the surface of the t-tubule.

Mentions: Model results in Figs. 4–5 were computed for conditions approximating those of the experiment by Cheng et al. [5], who examined Ca2+ signals in voltage-clamped rat myocytes in the presence of 100 µM Fluo-3 and pharmacological blockade of the SR (see Fig. 4L). The computed line-scan images and local Ca2+ time-courses are shown in Figs. 4F–4K.


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)

Calcium signals arising from the ionic fluxes via the external and t-tubule membrane in the presence of 100 µM Fluo-3.(A–B) The voltage-clamp protocol and whole-cell L-type Ca2+ current. (C–E) Predicted global Na+/Ca2+ and Ca2+ leak currents and global Ca2+ transient when no detectible differences in [Ca2+]i are found (see panel F). (F–H) Calcium concentrations visualized as line-scan images in transverse cell direction. (I–K) Local Ca2+ transients taken at three featured spots along the scanning line of interest: 0.17 µm – blue lines; 3.09 µm – green lines; 5.45 µm – red lines. In (F) and (I) the L-type Ca2+ current density followed heterogeneous distribution along the length of t-tubule as shown in Fig. 2A. In (G) and (J) the L-type Ca2+ current density was uniform along the t-tubule and six times higher than in external membrane. In (H) and (K) the L-type Ca2+ current density was homogeneous throughout the cell surface. In (F–G) Na+/Ca2+ flux density was three times higher in the t-tubule and Ca2+ leak homogeneously distributed. In (H) Na+/Ca2+ exchanger and Ca2+ leak were homogeneously distributed via the sarcolemma. (L) Local Ca2+ time-courses with re-plot from experimental data [5]. The re-plots were taken along the scanned line at 0µm (blue), 3.96 µm (green) and 5.65 µm (red) from the near surface location. (M) Estimated SCH values with respect to the three flux distribution choices. In this numerical experiment the line-scan was positioned at 200nm away from the t-tubule membrane at the angle 120°. The scanned line in Cheng et al. experiment was located at 200nm from the surface of the t-tubule.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2965743&req=5

pcbi-1000972-g004: Calcium signals arising from the ionic fluxes via the external and t-tubule membrane in the presence of 100 µM Fluo-3.(A–B) The voltage-clamp protocol and whole-cell L-type Ca2+ current. (C–E) Predicted global Na+/Ca2+ and Ca2+ leak currents and global Ca2+ transient when no detectible differences in [Ca2+]i are found (see panel F). (F–H) Calcium concentrations visualized as line-scan images in transverse cell direction. (I–K) Local Ca2+ transients taken at three featured spots along the scanning line of interest: 0.17 µm – blue lines; 3.09 µm – green lines; 5.45 µm – red lines. In (F) and (I) the L-type Ca2+ current density followed heterogeneous distribution along the length of t-tubule as shown in Fig. 2A. In (G) and (J) the L-type Ca2+ current density was uniform along the t-tubule and six times higher than in external membrane. In (H) and (K) the L-type Ca2+ current density was homogeneous throughout the cell surface. In (F–G) Na+/Ca2+ flux density was three times higher in the t-tubule and Ca2+ leak homogeneously distributed. In (H) Na+/Ca2+ exchanger and Ca2+ leak were homogeneously distributed via the sarcolemma. (L) Local Ca2+ time-courses with re-plot from experimental data [5]. The re-plots were taken along the scanned line at 0µm (blue), 3.96 µm (green) and 5.65 µm (red) from the near surface location. (M) Estimated SCH values with respect to the three flux distribution choices. In this numerical experiment the line-scan was positioned at 200nm away from the t-tubule membrane at the angle 120°. The scanned line in Cheng et al. experiment was located at 200nm from the surface of the t-tubule.
Mentions: Model results in Figs. 4–5 were computed for conditions approximating those of the experiment by Cheng et al. [5], who examined Ca2+ signals in voltage-clamped rat myocytes in the presence of 100 µM Fluo-3 and pharmacological blockade of the SR (see Fig. 4L). The computed line-scan images and local Ca2+ time-courses are shown in Figs. 4F–4K.

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