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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.

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