Electrodiffusion in cardiac intercalated disc nanostructures alters cell-cell action potential transmission via...

Ephaptic coupling modulates and assists cardiac action potential (AP) propagation in conjunction with gap junctional coupling. Ephaptic interactions rely on negative extracellular potentials within narrow intercellular clefts in intercalated discs (IDs) which influence the Na⁺ current in the ID membranes through the mechanisms of self-activation, self-attenuation and Na⁺ transfer. To date, the effects of ion concentration changes and electrodiffusion within complex ID nanostructures remain unclear. To elucidate these effects, we developed a new finite element model of cardiac IDs separating two adjacent cardiomyocytes, which incorporates ion concentration changes according to the Kirchhoff-Nernst-Planck formalism. Our study builds up from flat IDs to realistic tortuous IDs. Different ID configurations with varying distributions of Na⁺ channels and gap junctions were investigated. Our simulations show that upon excitation of the pre-junctional cell, Na⁺ is largely depleted in the extracellular cleft in the presence of a central Na⁺ channel cluster. This Na⁺ depletion is accompanied by K⁺ accumulation and Cl^- depletion, restoring electroneutrality. However, forcing ion concentrations to remain constant strengthens ephaptic AP transmission. Ephaptic interactions are also reinforced by the efflux of Na⁺ ions through the pre-junctional membrane into the ID cleft (Na⁺ transfer mechanism) and by sealing off the ephapses (higher access resistance to the cleft). Moreover, narrow clefts are crucial when Na⁺ channel clusters are distributed towards the periphery of the ID. Importantly, ephaptic coupling assists AP propagation in realistic tortuous IDs. In conclusion, our model contributes to the understanding of the impact of ephaptic coupling on cardiac conduction at the nanoscale. KEY POINTS: Ephaptic coupling is a cardiac conduction mechanism that involves negative extracellular potentials occurring in narrow intercalated disc (ID) clefts. We developed a new computational model of a cell pair that provides an unprecedented level of structural and functional electrophysiological detail of the ID. As the ID cleft is depleted from Na⁺, the direction of the Na⁺ current can change from inward to outward, which then brings new Na⁺ ions into the ID cleft, assisting ephaptic coupling. Perinexi and regions of dense extracellular proteins that partially seal off Na⁺ channel clusters reinforce ephaptic coupling by increasing extracellular potential changes due to a higher access resistance to the clusters. Our simulations demonstrate that the detailed ultrastructure of the ID plays a complex but important role in regulating AP transmission via ephaptic coupling.