Journal
FRONTIERS IN PHYSIOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2019.01487
Keywords
cardiomyocytes; transverse tubules; action potential; voltage-gated sodium channels; voltage-gated calcium channels
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Funding
- Swiss National Science Foundation [310030_165741, 310030_184707]
- Swiss National Science Foundation (SNF) [310030_184707, 310030_165741] Funding Source: Swiss National Science Foundation (SNF)
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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, while diseased T-tubules depolarize faster than healthy ones due to tubule widening. Increasing the tubule length non-linearly delays the depolarization. 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 -40 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. The intraluminal potential and sodium current self-attenuation however greatly depend on sodium current conductance. These results show that (1) the changes in passive electrical properties of remodeled T-tubules cannot explain the excitation-contraction coupling defects in diseased cells; and (2) the sodium current may modulate intraluminal potentials. Such extracellular potentials might also affect excitation-contraction coupling and macroscopic conduction.
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