Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc
File(s)Nature Communications,2016.pdf (1.96 MB)
Published version
Author(s)
Type
Journal 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.
Date Issued
2016-01-20
Date Acceptance
2015-12-01
Citation
Nature Communications, 2016, 7
ISSN
2041-1723
Publisher
Nature Research
Journal / Book Title
Nature Communications
Volume
7
Copyright Statement
This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
License URL
Sponsor
Biotechnology and Biological Sciences Research Council (BBSRC)
Wellcome Trust
British Heart Foundation
Biotechnology and Biological Sciences Research Council (BBSRC)
Biotechnology and Biological Sciences Research Cou
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000371043100001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
BB/L005816/1
090637/Z/09/Z
RG/12/18/30088
C19021
BB/D020875/1
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
Publication Status
Published
Article Number
ARTN 10919