Key result
T-tubular constrictions delay depolarization and generate negative potentials up to -50 mV that attenuate sodium current.
Why the study?
To address two largely unanswered questions regarding T-tubular electrical properties in health and disease: the delay of membrane depolarization and the effects of sodium current on intraluminal potentials.
This computational study demonstrates that T-tubular structural constrictions profoundly slow local depolarization, and that T-tubular sodium currents can create significant negative intraluminal potentials, highlighting the complex electrical nanodomains of diseased cardiomyocytes.
T-tubular constrictions may impair depolarization via negative potentials in HF models; challenges remodeling consensus and leaves open EC coupling mechanisms.
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. Here, 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. These 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.
No takes yet. Share an insight, caveat, or question.
Vermij et al. (2019) studied Cardiac T-tubular electrophysiology. Computational modeling of T-tubular constrictions and sodium current vs. Models of healthy, unconstricted T-tubules was evaluated on Delay of T-tubular membrane depolarization and intraluminal potentials. Constrictions greatly delayed T-tubular depolarization, while modeled T-tubular sodium current generated negative extracellular potentials (up to -50 mV in constricted tubules) that self-attenuated sodium channel function.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: