Modeling depolarization delay, sodium currents, and electrical potentials in cardiac transverse tubules

Abstract

T-tubules are invaginations of the lateral membrane of striated muscle cells that provide a large surface for ion channels and signaling proteins, thereby supporting excitation-contraction coupling. T-tubules are often remodeled in heart failure. To better understand the electrical behavior of T-tubules of cardiac cells in health and disease, this study addresses two largely unanswered questions regarding their electrical properties: (1) the delay of T-tubular membrane depolarization and (2) the effects of T-tubular sodium current on T-tubular potentials.\n\nHere, we present an elementary computational model to determine the delay in depolarization of deep T-tubular membrane segments as the narrow T-tubular lumen provides resistance against the extracellular current. We compare healthy tubules to tubules with constrictions and diseased tubules from mouse and human, and conclude that constrictions greatly delay T-tubular depolarization, and diseased T-tubules depolarize faster than healthy ones due to tubule widening. We moreover model the effect of T-tubular sodium current on intraluminal T-tubular potentials. We observe that extracellular potentials become negative during the sodium current transient (up to -50 mV in constricted T-tubules), which feedbacks on sodium channel function (self-attenuation) in a manner resembling ephaptic effects that have been described for intercalated discs where opposing membranes are very close together.\n\nThese results show that (1) the excitation-contraction coupling defects seen in diseased cells cannot be explained by T-tubular remodeling alone; and (2) the sodium current may modulate intraluminal potentials. Such extracellular potentials might also affect excitation-contraction coupling.