title: Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc.
abstract: 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.
authors.affiliation: 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.
authors.forename: Alejandra
authors.identifier: http://orcid.org/0000-0002-7579-9764
authors.initials: A
authors.lastname: Leo-Macias
authors.affiliation: 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.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Agullo-Pascual
authors.affiliation: 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.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Sanchez-Alonso
authors.affiliation: Center for Health Informatics and Bioinformatics, NYU-SoM, Translational Research Building, 227 East 30th Street, New York, New York 10016, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Keegan
authors.affiliation: 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.
authors.forename: Xianming
authors.initials: X
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Arcos
authors.affiliation: Microscopy Core, NYU-SoM, 522 First Avenue, Skirball Institute, 2nd Floor, New York, New York 10016, USA.
authors.lastname: Feng-Xia-Liang
authors.affiliation: Division of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, London W12 0NN, UK.
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Korchev
authors.affiliation: 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.
authors.forename: Julia
authors.initials: J
authors.lastname: Gorelik
authors.affiliation: Center for Health Informatics and Bioinformatics, NYU-SoM, Translational Research Building, 227 East 30th Street, New York, New York 10016, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fenyö
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU-SoM, 522 First Avenue, MSB 3rd Floor, New York, New York 10016, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Rothenberg
authors.forename: Eli
authors.initials: E
authors.lastname: Rothenberg
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D018408:Patch-Clamp Techniques; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D015820:Cadherins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D061566:Voltage-Gated Sodium Channels