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 NaV1.5. We show that the N-cadherin-NaV1.5 association is not random, that NaV1.5 molecules in these clusters are major contributors to cardiac sodium current, and that loss of NaV1.5 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.
[…] Fluorescent beads (0.1 μm diameter, Life Technologies) were adsorbed on a coverglass surface at a low density. A z-stack image was generated by acquiring images at 10 nm z-intervals, ranging from −500 to 500 nm considering 0 when the beads were in focus. A 3D calibration table with the ‘PSF Width minus Height' values over the z-position was created using the plugin QuickPALM on ImageJ (). […]
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