Contributions of Structural t-Tubule Heterogeneities and Membrane Ca 2+ Flux Localization to Local Ca 2+ Signaling in Rabbit Ventricular Myocytes

Abstract

The micro-architecture of the transverse tubular system (t-system) and the arrangement of associated proteins are central to the function of ventricular cardiomyocytes. Recently, confocal imaging and image processing was used to characterize the geometry of the t-system in rabbit ventricular cells [1]. The average diameter of single t-tubules was estimated to be 448+-172 nm with constrictions occurring every 1.87+-1.09 um along their principal axis. Here, we used mathematical modeling to investigate how local variations in t-tubular cross-sectional area and the distribution of membrane Ca2+flux regulate Ca2+-entry, diffusion and buffering in rabbits [2]. The current model includes a realistic geometry of a single t-tubule, its surrounding half-sarcomeres, the spatially distributed Ca2+transporting proteins along the cell membrane (L-type Ca2+ channel, Na+/Ca2+ exchanger, sarcolemmal Ca2+ pump) as well as stationary and mobile Ca2+ buffers (troponin C, ATP, calmodulin, Fluo-3). A finite element software package CSMOL was used to solve the coupled reaction-diffusion PDE system describing the time-dependent concentration profiles of the above-listed species.[3]. The model was parameterized according to voltage-clamp data in rabbit ventricular myocytes with Ca2+ release at the sarcoplasmic reticulum disabled pharmacologically [4]. The results indicate that the constrictions and spatial arrangements of membrane Ca2+ proteins may cause local inhomogeneities in Ca2+ concentration. In addition, we examined the activation of a catalytic Ca2+-binding site on Na+/Ca2+ exchanger on local Ca2+ gradients in the presence or absence of fluorescent dye.[1]Savio-Galimberti et al., Biophys J 95:2053-2062,2008.[2]Chenget al., PLoS CompBiol 2010, (in press).[3]SmoluchowskiSolver (CSMOL), http://mccammon.ucsd.edu/smol/[4]Sobie et al., Biophys J: Biophys Lett:L54-L56,2008.Supported by NBCR (NIH grant 2 P41 RR08605), NIHGM31749, NSFMCB-0506593,MCA93S013, Center for Theoretical Biological Physics, HHMI, SDSC, W. M. Keck foundation, and the Nora Eccles Harrison CardiovascularResearch and Training Institute