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Nat Commun. 2016 Jan 20;7:10342. doi: 10.1038/ncomms10342.

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

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The Leon H Charney Division of Cardiology, New York University School of Medicine (NYU-SoM), 522 First Avenue, Smilow 805, New York, New York 10016, USA.
Imperial College, National Heart and Lung Institute, Department of Cardiac Medicine, Imperial Center for Translational and Experimental Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Center for Health Informatics and Bioinformatics, NYU-SoM, Translational Research Building, 227 East 30th Street, New York, New York 10016, USA.
Microscopy Core, NYU-SoM, 522 First Avenue, Skirball Institute, 2nd Floor, New York, New York 10016, USA.
Division of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, London W12 0NN, UK.
Department of Biochemistry and Molecular Pharmacology, NYU-SoM, 522 First Avenue, MSB 3rd Floor, New York, New York 10016, USA.


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.

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