The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30106376.
- Also identified by DOI 10.7554/eLife.37610 and PMC identifier 6122953.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) -mediated adhesion scaffolds <i>trans</i>-activating Na<sub>V</sub>1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with Na<sub>V</sub>1.5. Smart patch clamp (SPC) indicated greater sodium current density (I<sub>Na</sub>) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, βadp1, potently and selectively inhibited β1-mediated adhesion, in electric cell-substrate impedance sensing studies. βadp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal I<sub>Na</sub>, but not whole cell I<sub>Na</sub>, in myocyte monolayers. In optical mapping studies, βadp1 precipitated arrhythmogenic conduction slowing. In summary, β1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.
Medical subject headings
- Arrhythmias, Cardiac
- Cell Communication
- Gap Junctions
- Myocytes, Cardiac