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.
Highlights
Intercellular adhesion and electrical excitability are considered separate cellular properties
Studies in cardiac tissue preparations, have shown that molecules conventionally defined as belonging to the voltage-gated sodium channels (VGSCs) can co-precipitate with mechanical junction proteins[1,2,3,4], and that loss of expression or mutations in specific proteins of the area composita[5] or of the costamere lead to a reduction in sodium current amplitude[4,6,7,8]
A complete solution of the three-dimensional (3D) structure of the intercalated disc (ID) using focused ion beam scanning electron microscopy (FIB-SEM) allows us to compare the dimensionality of the observed NaV1.5 clusters with that of the entire ID and examine whether the current magnitudes expected from the anatomical observations correspond to those previously recorded at the microscale[13]
Summary
Intercellular adhesion and electrical excitability are considered separate cellular properties. This complex cellular domain, comprising several sub-domains of tightly packed clusters of molecules[5,11,12], is highly relevant for intercellular communication and for cell excitability; sodium channels in this region are thought to carry most of the burden of propagation[13], and a role for ID sodium channels in cell–cell propagation has been proposed[14,15,16] The latter hypothesis (electric field-mediated cell–cell propagation) critically depends on the actual position and organization of the sodium channels within the vast complexity of the ID structure[15,16,17]. The close physical proximity between the VGSC and the N-cadherin-rich region lead us to speculate that just as mechanical junction proteins affect the sodium current[6,19,25], NaV1.5 may influence intercellular adhesion strength (IAS) These experiments unveil a novel non-canonical function for NaV1.5 These experiments unveil a novel non-canonical function for NaV1.5 (ref. 26), with possible implications to the understanding of the mechanisms responsible for structural heart disease associated with NaV1.5 mutations[27,28,29]
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