Effects of Membrane Calcium Flux Localizations and Realistic T-Tubule Geometry on Cardiac Excitation-Contraction Coupling

Abstract

The sub-cellular anatomy and ionic flux distributions are considered important in calcium (Ca) regulation and their variations over time may hold clues to the progression of heart diseases. To investigate how these coupled processes may affect the cardiac cell function we developed 3D continuum model of Ca-signaling, buffering and diffusion in rat ventricular myocytes. The model geometry was derived from high definition light and electron microscopy images in rodent cardiac cells through a process called tomographic reconstruction [1, 2]. The current model includes: the 3D geometry of a single t-tubule and its surrounding half-sarcomeres; spatially distributed Ca handling proteins along the t-tubule and surface membrane; stationary and mobile Ca buffers (ATP, calmodulin, fluo-3, troponin C). A finite element software package SMOL-SubCell was used to solve the PDE system on cluster of computers [3]. In agreement with experiment [4,5], model suggests that the rat t-tubule anatomy and the heterogeneous distribution of Ca fluxes along the cell membrane might be important mechanisms for maintaining uniform Ca concentration in presence of 100 microM fluo-3 and sarcoplasmic reticulum inhibited. In the absence of fluo-3, model predicts that the overall Ca distribution can not be maintained uniform when the membrane Ca fluxes were heterogeneously distributed.[1] Hayashi et al., J Cell Science 122:1005-1013, 2009.[2] Yu et al., J Structural Biol 164:304-313, 2008.[3] Smoluchowski Solver (SMOL), http://mccammon.ucsd.edu/smol/[4] Scriven et al., Ann NY Acad Sci 976:488-499, 2002.[5] Cheng et al., Pflugers Arch 428:415-417, 1994.Supported by NBCR (NIH grant 2 P41 RR08605), NIH GM31749, NSF MCB-0506593, MCA93S013, Howard Hughes Medical Institute, SDSC, Accelrys, inc., W. M. Keck foundation.∗Corresponding author: amihaylo@ucsd.edu