Modeling Calcium Dynamics in Rabbit Ventricular Myocytes with Several Realistic T-Tubules Subject to Detubulation

Abstract

Calcium signaling in cardiomyocytes is strongly influenced by the topology of the sarcolemma (SL) and the distribution and clustering of sarcolemmal Ca2+ transporters, including the L-type Ca2+ channel (LCC) and sodium-calcium exchanger (NCX). Cardiac ventricular myocytes contain dense networks of cell membrane invaginations called t-tubules (TTs), which contain SL transporters that trigger Ca2+ release from the channel of the sarcoplasmic reticulum (SR), known as ryanodine receptor (RyR). The TT network ensures uniformity of the Ca2+ transient, and pathological remodeling of TT-network produces heterogeneous Ca2+ transients. This remodeling reduces the density of SL Ca2+ transporters and perturbs the topology of the space into which Ca2+ diffuses. The extent to which these factors contribute to the non-uniform Ca2+ transient observed in remodeled cells is however unclear. In this study, we examined a 9x5x6 µm subcellular region of a rabbit ventricular myocyte with confocal microscope. We inferred LCC cluster distribution statistics from localized RyR clusters data. We solved time-dependent reaction-diffusion equations describing important sources of sarcolemmal transport and cytosolic buffering and diffusion of Ca2+. We found that the local Ca2+ gradients’ profiles are influenced predominantly by the distribution of SL Ca2+ transporters and secondarily by the configuration of TTs. Our results also suggest that the early stages of the Ca2+ transient, prior to SR release, are sensitive to LCC cluster distribution and TT configuration.Supported by NBCR (NIH grant 2 P41 GM103426-19), NIH GM31749, NSF MCB-1020765, MCA93S013, Center for Theoretical Biological Physics, Howard Hughes Medical Institute, SDSC, W. M. Keck foundation, Nora Eccles Harrison Cardiovascular Research and Training Institute.