Veeraraghavan, RengasayeeHoeker, Gregory S.Alvarez-Laviada, AnitaHoagland, Daniel T.Wan, XiaopingKing, D. RyanSanchez-Alonso, JoseChen, ChunlingJourdan, L. JaneIsom, Lori L.Deschenes, IsabelleSmith, James W.Gorelik, JuliaPoelzing, StevenGourdie, Robert G.2019-10-182019-10-182018-08-142050-084Xe37610http://hdl.handle.net/10919/94638Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that beta 1(SCN1B) - mediated adhesion scaffolds trans-activating Na(V)1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential beta 1 localization at the perinexus, where it co-locates with Na(V)1.5. Smart patch clamp (SPC) indicated greater sodium current density (I-Na) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, beta adp1, potently and selectively inhibited beta 1-mediated adhesion, in electric cell-substrate impedance sensing studies. beta adp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal I-Na, but not whole cell I-Na, in myocyte monolayers. In optical mapping studies, beta adp1 precipitated arrhythmogenic conduction slowing. In summary, beta 1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.application/pdfenCreative Commons Attribution 4.0 Internationalendothelial barrier functionintercalated discgap-junctionsmyocardial-cellsfluorescence microscopyventricular myocytesatrial-fibrillationbrugada syndromealpha-subunitsamino-acidsArticle - Refereedhttps://doi.org/10.7554/eLife.37610730106376