Year: 2016
Type: article
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.
Source: Nature Communications
DOI: 10.1038/ncomms10342
Institutions: New York University, Imperial College London
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Simons Foundation, American Heart Association, Arnold and Mabel Beckman Foundation, Heart Rhythm Society, NYU Langone Medical Center, Agouron Institute, Wellcome Trust, British Heart Foundation, Fondation Leducq, National Institutes of Health, Centers for Disease Control and Prevention, Biotechnology and Biological Sciences Research Council, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Center for Research Resources
Awards: Role of Desmosomes in Cardiac Electrical Function, Acquisition of Detector for JEOL 3200 FSC Electron Microscope, A gap junction-independent role for Connexin43 in cardiac electrophysiology, Development of high-speed SICM for biological applications., Single-molecule studies of BRCA1-BACH1 mechanism in genomic integrity, Single-Molecule Studies of Human RECQ5 Helicase Mechanisms, G2741619365, G317091481, G3424582138, G3789973434, 300 kV Electron Microscope for Structural Biology, G4298014510, Dual-Beam Scanning Electron Microscope for New York Structural Biology Center, cAMP/cGMP localisation in cardiac myocytes by a new nanoscale multifunctional scanning technique, G4931614974, G5004220402, G5113856918, G5250076473, G533446661, Single-Molecule Studies of Non-Homologous DNA End Joining, G6051507980, G6715624472, G6845228078, Development of SICM for single channel recording in brain slices., EXTRAMURAL RESEARCH FACILITIES CONSTRUCTION, Development of the next generation of sicm for live cell imaging, G8791006661, G9000036756, G9000108157, G9000215172, G9000275336
OpenAlex ID: W2301058553