Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc

Intercellular adhesion and electrical excitability are considered separate cellular properties. Studies of myelinated fibres, however, show that voltage-gated sodium channels (VGSCs) aggregate with cell adhesion molecules at discrete subcellular locations, such as the nodes of Ranvier. Demonstration of similar macromolecular organization in cardiac muscle is missing. Here we combine nanoscale-imaging (single-molecule localization microscopy; electron microscopy; and ‘angle view’ scanning patch clamp) with mathematical simulations to demonstrate distinct hubs at the cardiac intercalated disc, populated by clusters of the adhesion molecule N-cadherin and the VGSC Na V 1.5. We show that the N-cadherin-Na V 1.5 association is not random, that Na V 1.5 molecules in these clusters are major contributors to cardiac sodium current, and that loss of Na V 1.5 expression reduces intercellular adhesion strength. We speculate that adhesion/excitability nodes are key sites for crosstalk of the contractile and electrical molecular apparatus and may represent the structural substrate of cardiomyopathies in patients with mutations in molecules of the VGSC complex. In myelinated fibres conduction and adhesion proteins aggregate at discrete foci, but it is unclear if this organization is present in other excitable cells. Using nanoscale visualization and in silico techniques, the authors show that adhesion/excitability nodes exist at the intercalated discs of adult cardiac muscle.