Modeling Calcium Dynamics in Realistic Rabbit Ventricular Myocytes with Several Transverse Tubules

Abstract

Calcium signaling in cardiomyocytes is strongly influenced by the topology of the sarcolemma (SL) and the distribution of sarcolemmal proteins, including the L-type calcium channel (LCC) and sodium-calcium exchanger (NCX). Peculiar to mammalian ventricular cardiomyocytes are sarcolemmal invaginations called transverse tubules (TT) exhibiting high densities of LCC clusters that trigger Ca2+ release from the sarcoplasmic reticulum (SR). Prior studies of pharmacologically-disabled SR release in rabbit ventricular myocytes have demonstrated that sub-micrometer resolution details of the SL geometry shape local Ca2+ dynamics and suggest a feedback between cytosolic [Ca2+] and SL ion channel and transporter activity. Here we investigate the hypothesis that the ordered spatial arrangement of TT and coupling between adjacent tubules leads to an organized Ca2+ transient. Moreover, we compare Ca2+ transients arising from clustered or continuously-distributed trigger fluxes for the propensity to produce Ca2+ waves. Our findings are that 1) the arrangement of TTs promotes a faster rise in [Ca2+] transversely relative to the longitudinal direction of cardiomyocytes and 2) clustering of SL transporters along the TT promotes an axially-uniform calcium transient. These results evidence contribution of structural detail at sub-micrometer resolution to excitation-contraction coupling and anomalous Ca2+ dynamics underlying cardiac arrhythmias.Supported by NBCR (NIH grant 2 P41 RR08605), NIH GM31749, NSF MCB-0506593, MCA93S013, Center for Theoretical Biological Physics, Howard Hughes Medical Institute, SDSC, W. M. Keck foundation, Richard A. and Nora Eccles Fund for Cardiovascular Research.