Modeling Effects of L-Type Ca2+ Current and Na+-Ca2+ Exchanger on Ca2+ Trigger Flux in Rabbit Myocytes with Realistic T-Tubule Geometries

• Published in: Frontiers in physiology Vol. 3
• Main Authors: Kekenes-Huskey, Peter M., Cheng, Yuhui, Hake, Johan E., Sachse, Frank B., Bridge, John H., Holst, Michael J., McCammon, J. Andrew, McCulloch, Andrew D., Michailova, Anushka P.
• Format: Journal Article
• Language: English
• Published: Frontiers Research Foundation 01-01-2012; Frontiers Media S.A
• Subjects: Allosteric Regulation; Ca2+ signaling; channel clustering; L-type Ca2+ channel; Na+/Ca2+ exchanger; Physiology; rabbit ventricular myocyte
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2012.00351

The transverse tubular system of rabbit ventricular myocytes consists of cell membrane invaginations (t-tubules) that are essential for efficient cardiac excitation-contraction coupling. In this study, we investigate how t-tubule micro-anatomy, L-type Ca
2+
channel (LCC) clustering, and allosteric activation of Na
+
/Ca
2+
exchanger by L-type Ca
2+
current affects intracellular Ca
2+
dynamics. Our model includes a realistic 3D geometry of a single t-tubule and its surrounding half-sarcomeres for rabbit ventricular myocytes. The effects of spatially distributed membrane ion-transporters (LCC, Na
+
/Ca
2+
exchanger, sarcolemmal Ca
2+
pump, and sarcolemmal Ca
2+
leak), and stationary and mobile Ca
2+
buffers (troponin C, ATP, calmodulin, and Fluo-3) are also considered. We used a coupled reaction-diffusion system to describe the spatio-temporal concentration profiles of free and buffered intracellular Ca
2+
. We obtained parameters from voltage-clamp protocols of L-type Ca
2+
current and line-scan recordings of Ca
2+
concentration profiles in rabbit cells, in which the sarcoplasmic reticulum is disabled. Our model results agree with experimental measurements of global Ca
2+
transient in myocytes loaded with 50 μM Fluo-3. We found that local Ca
2+
concentrations within the cytosol and sub-sarcolemma, as well as the local trigger fluxes of Ca
2+
crossing the cell membrane, are sensitive to details of t-tubule micro-structure and membrane Ca
2+
flux distribution. The model additionally predicts that local Ca
2+
trigger fluxes are at least threefold to eightfold higher than the whole-cell Ca
2+
trigger flux. We found also that the activation of allosteric Ca
2+
-binding sites on the Na
+
/Ca
2+
exchanger could provide a mechanism for regulating global and local Ca
2+
trigger fluxes
in vivo
. Our studies indicate that improved structural and functional models could improve our understanding of the contributions of L-type and Na
+
/Ca
2+
exchanger fluxes to intracellular Ca
2+
dynamics.