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Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc
Alejandra Leo-Macias1, Esperanza Agullo-Pascual1, Jose L Sanchez-Alonso2
1The 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.
Nature Communications
|January 21, 2016
Summary
Cardiac cells organize adhesion molecules and sodium channels at intercalated discs, impacting electrical activity and cell adhesion. This discovery reveals new insights into heart function and disease.
Area of Science:
- Cardiovascular Biology
- Cellular Electrophysiology
- Molecular Cardiology
Background:
- Intercellular adhesion and electrical excitability were traditionally viewed as distinct cellular functions.
- Previous studies in myelinated fibers indicated voltage-gated sodium channels (VGSCs) aggregate with cell adhesion molecules at specific sites like nodes of Ranvier.
- Similar macromolecular organization had not been demonstrated in cardiac muscle.
Purpose of the Study:
- To investigate the co-localization and functional interaction of cell adhesion molecules and voltage-gated sodium channels in cardiac muscle.
- To determine if cardiac intercalated discs contain organized clusters of N-cadherin and NaV1.5, similar to nodes of Ranvier in nerve fibers.
- To explore the functional consequences of this association on cardiac sodium current and intercellular adhesion.
Main Methods:
- Utilized advanced nanoscale imaging techniques, including single-molecule localization microscopy and electron microscopy.
- Employed 'angle view' scanning patch clamp electrophysiology.
- Integrated mathematical simulations to analyze molecular organization and function.
Main Results:
- Demonstrated distinct hubs at the cardiac intercalated disc containing clusters of N-cadherin and the voltage-gated sodium channel NaV1.5.
- Established that the N-cadherin-NaV1.5 association is specific and not random.
- Showed that NaV1.5 molecules within these clusters significantly contribute to cardiac sodium current.
- Found that reduced NaV1.5 expression weakens intercellular adhesion strength.
Conclusions:
- Cardiac intercalated discs feature organized 'adhesion/excitability nodes' comprising N-cadherin and NaV1.5.
- These nodes are crucial for integrating electrical and mechanical functions in the heart.
- Dysfunction in these nodes may underlie cardiomyopathies associated with mutations in VGSC complex molecules.
