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

Abstract

It has been proposed that ephaptic interactions in intercalated discs, mediated by extracellular potentials, contribute to cardiac impulse propagation when gap junctional coupling is reduced. However, experiments demonstrating ephaptic effects on the cardiac Na⁺ current (I_Na) are scarce. Furthermore, Na⁺ channels form clusters around gap junction plaques, but the electrophysiological significance of these clusters has never been investigated. In patch clamp experiments with HEK cells stably expressing human Na_v1.5 channels, we examined how restricting the extracellular space modulates I_Na elicited by an activation protocol. In parallel, we developed a high-resolution computer model of the intercalated disc to investigate how the distribution of Na⁺ channels influences ephaptic interactions. Approaching the HEK cells to a non-conducting obstacle always increased peak I_Na at step potentials near the threshold of I_Na activation and decreased peak I_Na at step potentials far above threshold (7 cells, P = 0.0156, Wilcoxon signed rank test). These effects were consistent with corresponding control simulations with a uniform Na⁺ channel distribution. In the intercalated disc computer model, redistributing the Na⁺ channels into a central cluster of the disc potentiated ephaptic effects. Moreover, ephaptic impulse transmission from one cell to another was facilitated by clusters of Na⁺ channels facing each other across the intercellular cleft when gap junctional coupling was reduced. In conclusion, our proof-of-principle experiments demonstrate that confining the extracellular space modulates cardiac I_Na, and our simulations reveal the functional role of the aggregation of Na⁺ channels in the perinexus. These findings highlight novel concepts in the physiology of cardiac excitation.

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