Sodium channel subpopulations with distinct biophysical properties and subcellular localization enhance cardiac conduction

Sodium (Na+) current is responsible for the rapid depolarization of cardiac myocytes that triggers the cardiac action potential upstroke. Recent studies have illustrated the presence of multiple “pools” of Na+ channels with distinct biophysical properties and subcellular localization, including clustering of channels at the intercalated disk and along the lateral membrane. Computational studies predict that Na+ channel clusters at the intercalated disk can regulate cardiac conduction via modulation of the narrow intercellular cleft between electrically coupled myocytes. However, these studies have primarily focused on the redistribution of Na+ channels between intercalated disk and lateral membranes and not considered the distinct biophysical properties of the Na+ channel subpopulations. In this study, we simulate computational models of single cardiac cells and one-dimensional cardiac tissues to predict the functional consequence of distinct Na+ channel subpopulations. Single cell simulations predict that a subpopulation of Na+ channels with shifted steady-state activation and inactivation voltage-dependency promote an earlier action potential upstroke. In cardiac tissues that account for distinct subcellular spatial localization, simulations predict that “shifted” Na+ channels contribute to faster and more robust conduction, with regards to sensitivity to tissue structural changes (i.e., cleft width), gap junctional coupling, and rapid pacing rates. Simulations predict that the intercalated disk-localized shifted Na+ channels provide a disproportionally larger contribution to total Na+ charge, relative to lateral membrane-localized Na+ channels. Importantly, our work supports the hypothesis that Na+ channel redistribution may be a critical mechanism by which cells can rapidly respond to perturbations to support fast and robust conduction. Summary Sodium channels are organized in multiple “pools” with distinct biophysical properties and subcellular localization, but the role of these subpopulations is not well-understood. Computational modeling predicts that intercalated disk-localized sodium channels with shifted steady-state activation and inactivation voltage-dependence promote faster cardiac conduction. ### Competing Interest Statement The authors have declared no competing interest.