v 1.5 recordings from cardiomyocyte-cardiomyocyte and cardiomyocyte-fibroblasts junctions. Functional and dominant-negative Cx43 EGFP adenoviruses were used to probe active/inactive junctions. The Na v b1 adhesion inhibitor peptide (badp1) was tested. Whole-cell Na v -currents were recorded to separate non-junctional badp1 effects. To assess transdepolarisation, current-clamp and optical measurements were combined. Plasma membranes were analysed for junctional protein density. Exogenously-delivered Cx43 EGFP trafficked to regions where Na v activity and cluster size were increased relative to native Cx43-junctions (p=0.015). Smaller Na v -clusters (5-10) were abundant at native junctions, larger clusters (20-30) predominated at Cx43 EGFP -junctions. Acute badp1 peptide treatment caused Na v downregulation at native (p<0.01) and Cx43 EGFP -rich junctions (p<0.001). Lack of badp1 effect on the whole-cell current supports a role for b1 as a trans-cellular adhesion molecule. Blockade of cardiomyocyte transactivation using optical/electrical recordings was demonstrated with badp1 pre-treatment. Reduced Na v -current and smaller channel clusters were found at cardiomyocyte-fibroblast versus cardiomyocyte-cardiomyocytes junctions. Membranes from junction-remote regions showed similar currents, but different Na v -cluster size. Strength of intercellular junctions depend on Na v -current, intact Na v b1 and the amount of functional Cx43. Cardiac junction type hetero-vs. homo-cellular governs Na v activity and distribution. Novel badp1 peptide establishes importance of perinexal regions for signal propagation. Our findings and biophysical approach elucidate molecular origin of arrhythmogenic activity within/around GJ, revealing rationale for the anti-arrhythmic effects of Na v b1-mediated adhesion.
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