Sodium channels in the Cx43 gap junction perinexus may constitute a cardiac ephapse: an experimental and modeling study

dc.contributor.authorVeeraraghavan, Rengasayeeen
dc.contributor.authorLin, Joyceen
dc.contributor.authorHoeker, Gregory S.en
dc.contributor.authorKeener, James P.en
dc.contributor.authorGourdie, Robert G.en
dc.contributor.authorPoelzing, Stevenen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentSchool of Biomedical Engineering and Sciencesen
dc.date.accessioned2017-02-03T15:06:39Zen
dc.date.available2017-02-03T15:06:39Zen
dc.date.issued2015-10-01en
dc.description.abstractIt has long been held that electrical excitation spreads from cell-to-cell in the heart via low resistance gap junctions (GJ). However, it has also been proposed that myocytes could interact by non-GJ-mediated “ephaptic” mechanisms, facilitating propagation of action potentials in tandem with direct GJmediated coupling. We sought evidence that such mechanisms contribute to cardiac conduction. Using super-resolution microscopy, we demonstrate that Nav1.5 is localized within 200 nm of the GJ plaque (a region termed the perinexus). Electron microscopy revealed close apposition of adjacent cell membranes within perinexi suggesting that perinexal sodium channels could function as an ephapse, enabling ephaptic cell-to-cell transfer of electrical excitation. Acute interstitial edema (AIE) increased intermembrane distance at the perinexus andwas associated with preferential transverse conduction slowing and increased spontaneous arrhythmia incidence. Inhibiting sodium channels with 0.5 μM flecainide uniformly slowed conduction, but sodium channel inhibition during AIE slowed conduction anisotropically and increased arrhythmia incidence more than AIE alone. Sodium channel inhibition during GJ uncoupling with 25 μM carbenoxolone slowed conduction anisotropically and was also highly proarrhythmic. A computational model of discretized extracellular microdomains (including ephaptic coupling) revealed that conduction trends associated with altered perinexal width, sodium channel conductance, and GJ coupling can be predicted when sodium channel density in the intercalated disk is relatively high. We provide evidence that cardiac conduction depends on a mathematically predicted ephaptic mode of coupling as well as GJ coupling. These data suggest opportunities for novel anti-arrhythmic therapies targeting noncanonical conduction pathways in the heart.en
dc.description.versionPublished versionen
dc.format.extent2093 - 2105 (13) page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1007/s00424-014-1675-zen
dc.identifier.issn0031-6768en
dc.identifier.issue10en
dc.identifier.urihttp://hdl.handle.net/10919/74918en
dc.identifier.volume467en
dc.language.isoenen
dc.publisherSpringeren
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000361000800005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectPhysiologyen
dc.subjectCardiac conductionen
dc.subjectArrhythmiaen
dc.subjectSodium channelsen
dc.subjectGap junctionsen
dc.subjectEphaptic couplingen
dc.subjectELECTRIC-FIELDen
dc.subjectIMPULSE PROPAGATIONen
dc.subjectINTERCALATED DISKSen
dc.subjectACTION-POTENTIALSen
dc.subjectMYOCARDIAL-CELLSen
dc.subjectSLOW CONDUCTIONen
dc.subjectKNOCKOUT MICEen
dc.subjectCONNEXIN43en
dc.subjectHEMICHANNELSen
dc.subjectMYOCYTESen
dc.titleSodium channels in the Cx43 gap junction perinexus may constitute a cardiac ephapse: an experimental and modeling studyen
dc.title.serialPflugers Archiv-European Journal Of Physiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Virginia Tech Carilion Research Instituteen
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