Localization of Na⁺ channel clusters in narrowed perinexi of gap junctions enhances cardiac impulse transmission via...

It has been proposed that when gap junctional coupling is reduced in cardiac tissue, action potential propagation can be supported via ephaptic coupling, a mechanism mediated by negative electric potentials occurring in narrow intercellular clefts of intercalated discs (IDs). Recent studies showed that sodium (Na⁺ ) channels form clusters near gap junction plaques in nanodomains called perinexi, where the ID cleft is even narrower. To examine the electrophysiological relevance of Na⁺ channel clusters being located in perinexi, we developed a 3D finite element model of two longitudinally abutting cardiomyocytes, with a central Na⁺ channel cluster on the ID membranes. When this cluster was located in the perinexus of a closely positioned gap junction plaque, varying perinexal width greatly modulated impulse transmission from one cell to the other, with narrow perinexi potentiating ephaptic coupling. This modulation occurred via the interplay of Na⁺ currents, extracellular potentials in the cleft and patterns of current flow within the cleft. In contrast, when the Na⁺ channel cluster was located remotely from the gap junction plaque, this modulation by perinexus width largely disappeared. Interestingly, the Na⁺ current in the ID membrane of the pre-junctional cell switched from inward to outward during excitation, thus contributing ions to the activating channels on the post-junctional ID membrane. In conclusion, these results indicate that the localization of Na⁺ channel clusters in the perinexi of gap junction plaques is crucial for ephaptic coupling, which is furthermore greatly modulated by perinexal width. These findings are relevant for a comprehensive understanding of cardiac excitation. KEY POINTS: Ephaptic coupling is a cardiac conduction mechanism involving nanoscale-level interactions between the sodium (Na⁺ ) current and the extracellular potential in narrow intercalated disc clefts. When gap junctional coupling is reduced, ephaptic coupling acts in conjunction with the classical cardiac conduction mechanism based on gap junctional current flow. In intercalated discs, Na⁺ channels form clusters that are preferentially located in the periphery of gap junction plaques, in nanodomains known as perinexi, but the electrophysiological role of these perinexi has never been examined. In our new 3D finite element model of two cardiac cells abutting each other with their intercalated discs, a Na⁺ channel cluster located inside a narrowed perinexus facilitated impulse transmission via ephaptic coupling. Our simulations demonstrate the role of narrowed perinexi as privileged sites for ephaptic coupling in pathological situations when gap junctional coupling is decreased.