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Modeling effects of L-type ca(2+) current and na(+)-ca(2+) exchanger on ca(2+) trigger flux in rabbit myocytes with realistic T-tubule geometries.


ABSTRACT: 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??M 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.

SUBMITTER: Kekenes-Huskey PM 

PROVIDER: S-EPMC3463892 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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Modeling effects of L-type ca(2+) current and na(+)-ca(2+) exchanger on ca(2+) trigger flux in rabbit myocytes with realistic T-tubule geometries.

Kekenes-Huskey Peter M PM   Cheng Yuhui Y   Hake Johan E JE   Sachse Frank B FB   Bridge John H JH   Holst Michael J MJ   McCammon J Andrew JA   McCulloch Andrew D AD   Michailova Anushka P AP  

Frontiers in physiology 20120910


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  ...[more]

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