Distribution of cardiac sodium channels in clusters potentiates ephaptic interactions in the intercalated disc

Hichri, Echrak; Abriel, Hugues; Kučera, Jan

doi:10.1113/jp275351

Cited by 60 publications

(109 citation statements)

References 47 publications

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“…This is explained by the very small T-tubule diameter. At the cardiac intercalated disc, where two opposing membranes are also very close together, a similar effect has been predicted (Rhett et al, 2013;Veeraraghavan et al, 2015;Hichri et al, 2018). Importantly, sodium depletion in the T-tubule caused by sodium entering the cell may even augment the sodium current self-attenuation by decreasing the Nernst potential of sodium.…”

Section: Discussionsupporting

confidence: 53%

Modeling Depolarization Delay, Sodium Currents, and Electrical Potentials in Cardiac Transverse Tubules

2019

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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 excitationcontraction 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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Section: Discussionsupporting

confidence: 53%

Modeling Depolarization Delay, Sodium Currents, and Electrical Potentials in Cardiac Transverse Tubules

2019

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“…Interestingly, Hichri and colleagues recently demonstrated that Na V 1.5 behavior is influenced by channel clustering, and localization facing narrow extracellular clefts (Hichri et al, 2018), raising the possibility of Na V 1.5 pools playing different, ultra-structure dependent roles. Here, using super-resolution STORM-RLA (Veeraraghavan and Gourdie, 2016), we further categorize ID-localized Na V 1.5 into a ‘perinexal pool’ adjacent to Cx43 and a ‘plicate pool’ that co-distributes with N-cad.…”

Section: Discussionmentioning

confidence: 99%

The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation

Veeraraghavan

Hoeker

Alvarez-Laviada

et al. 2018

eLife

101

173

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Computational modeling indicates that cardiac conduction may involve ephaptic coupling – intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) –mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with NaV1.5. Smart patch clamp (SPC) indicated greater sodium current density (INa) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, βadp1, potently and selectively inhibited β1-mediated adhesion, in electric cell-substrate impedance sensing studies. βadp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal INa, but not whole cell INa, in myocyte monolayers. In optical mapping studies, βadp1 precipitated arrhythmogenic conduction slowing. In summary, β1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.

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“…This is explained by the very small T-tubule diameter. At the cardiac intercalated disc, where two opposing membranes are also very close together, a similar effect has been predicted (Rhett et al, 2013;Veeraraghavan et al, 2015;Hichri et al, 2018). Importantly, sodium depletion in the T-tubule caused by sodium entering the cell may even augment the self-attenuation of the sodium current because this depletion will decrease the Nernst potential of sodium.…”

Section: Discussionmentioning

confidence: 54%

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

Vermij

Abriel

Kučera

2019

Preprint

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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, 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.

show abstract

Distribution of cardiac sodium channels in clusters potentiates ephaptic interactions in the intercalated disc

Cited by 60 publications

References 47 publications

Modeling Depolarization Delay, Sodium Currents, and Electrical Potentials in Cardiac Transverse Tubules

Modeling Depolarization Delay, Sodium Currents, and Electrical Potentials in Cardiac Transverse Tubules

The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation

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

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