The adhesion function of the sodium channel beta subunit (beta 1) contributes to cardiac action potential propagation

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dc.contributor.authorVeeraraghavan, Rengasayeeen
dc.contributor.authorHoeker, Gregory S.en
dc.contributor.authorAlvarez-Laviada, Anitaen
dc.contributor.authorHoagland, Daniel T.en
dc.contributor.authorWan, Xiaopingen
dc.contributor.authorKing, D. Ryanen
dc.contributor.authorSanchez-Alonso, Joseen
dc.contributor.authorChen, Chunlingen
dc.contributor.authorJourdan, L. Janeen
dc.contributor.authorIsom, Lori L.en
dc.contributor.authorDeschenes, Isabelleen
dc.contributor.authorSmith, James W.en
dc.contributor.authorGorelik, Juliaen
dc.contributor.authorPoelzing, Stevenen
dc.contributor.authorGourdie, Robert G.en
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentBiomedical Engineering and Mechanicsen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentVirginia Tech Carilion School of Medicineen
dc.date.accessioned2019-10-18T14:41:48Zen
dc.date.available2019-10-18T14:41:48Zen
dc.date.issued2018-08-14en
dc.description.abstractComputational 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.en
dc.description.notesNational Heart, Lung, and Blood Institute RO1 HL56728-15A2 Robert G Gourdie; American Heart Association 16SDG29870007 Rengasayee Veeraraghavan; National Heart, Lung, and Blood Institute R01 HL102298-01A1 Steven Poelzing; National Institutes of Health R01 HL102298-01A1 James W Smith; National Institutes of Health R37NS076752 Lori L Isom; National Heart, Lung, and Blood Institute RO1 HL HL141855-01 Robert G Gourdie Steven Poelzing; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.en
dc.description.sponsorshipNational Heart, Lung, and Blood InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [RO1 HL56728-15A2, R01 HL102298-01A1, RO1 HL HL141855-01]; American Heart AssociationAmerican Heart Association [16SDG29870007]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HL102298-01A1, R37NS076752]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.7554/eLife.37610en
dc.identifier.issn2050-084Xen
dc.identifier.othere37610en
dc.identifier.pmid30106376en
dc.identifier.urihttp://hdl.handle.net/10919/94638en
dc.identifier.volume7en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectendothelial barrier functionen
dc.subjectintercalated discen
dc.subjectgap-junctionsen
dc.subjectmyocardial-cellsen
dc.subjectfluorescence microscopyen
dc.subjectventricular myocytesen
dc.subjectatrial-fibrillationen
dc.subjectbrugada syndromeen
dc.subjectalpha-subunitsen
dc.subjectamino-acidsen
dc.titleThe adhesion function of the sodium channel beta subunit (beta 1) contributes to cardiac action potential propagationen
dc.title.serialeLifeen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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