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Ephaptic Coupling Is a Mechanism of Conduction Reserve During Reduced Gap Junction Coupling

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dc.contributor.authorLin, Joyceen
dc.contributor.authorAbraham, Ananden
dc.contributor.authorGeorge, Sharon A.en
dc.contributor.authorGreer-Short, Amaraen
dc.contributor.authorBlair, Grace A.en
dc.contributor.authorMoreno, Angelen
dc.contributor.authorAlber, Bridget R.en
dc.contributor.authorKay, Matthew W.en
dc.contributor.authorPoelzing, Stevenen
dc.date.accessioned2022-06-15T14:08:33Zen
dc.date.available2022-06-15T14:08:33Zen
dc.date.issued2022-05-05en
dc.description.abstractMany cardiac pathologies are associated with reduced gap junction (GJ) coupling, an important modulator of cardiac conduction velocity (CV). However, the relationship between phenotype and functional expression of the connexin GJ family of proteins is controversial. For example, a 50% reduction of GJ coupling has been shown to have little impact on myocardial CV due to a concept known as conduction reserve. This can be explained by the ephaptic coupling (EpC) theory whereby conduction is maintained by a combination of low GJ coupling and increased electrical fields generated in the sodium channel rich clefts between neighboring myocytes. At the same time, low GJ coupling may also increase intracellular charge accumulation within myocytes, resulting in a faster transmembrane potential rate of change during depolarization (dV/dt_max) that maintains macroscopic conduction. To provide insight into the prevalence of these two phenomena during pathological conditions, we investigated the relationship between EpC and charge accumulation within the setting of GJ remodeling using multicellular simulations and companion perfused mouse heart experiments. Conduction along a fiber of myocardial cells was simulated for a range of GJ conditions. The model incorporated intercellular variations, including GJ coupling conductance and distribution, cell-to-cell separation in the intercalated disc (perinexal width-W-P), and variations in sodium channel distribution. Perfused heart studies having conditions analogous to those of the simulations were performed using wild type mice and mice heterozygous null for the connexin gene Gja1. With insight from simulations, the relative contributions of EpC and charge accumulation on action potential parameters and conduction velocities were analyzed. Both simulation and experimental results support a common conclusion that low GJ coupling decreases and narrowing W-P increases the rate of the AP upstroke when sodium channels are densely expressed at the ends of myocytes, indicating that conduction reserve is more dependent on EpC than charge accumulation during GJ uncoupling.en
dc.description.notesThis work was supported by National Institutes of Health grants R01HL102298 (JL and SP) and R01HL146169 (MK) as well as American Heart Association Pre and Post-Doctoral Fellowships (SG).en
dc.description.sponsorshipNational Institutes of Health [R01HL102298, R01HL146169]; American Heart Association Pre and Post-Doctoral Fellowshipsen
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fphys.2022.848019en
dc.identifier.eissn1664-042Xen
dc.identifier.other848019en
dc.identifier.pmid35600295en
dc.identifier.urihttp://hdl.handle.net/10919/110785en
dc.identifier.volume13en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectcellular couplingen
dc.subjectpropagationen
dc.subjectgap junction remodelingen
dc.subjectmyocardiumen
dc.subjectsimulationen
dc.titleEphaptic Coupling Is a Mechanism of Conduction Reserve During Reduced Gap Junction Couplingen
dc.title.serialFrontiers in Physiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Scholarly Works, Virginia Tech Carilion School of Medicine (VTCSOM)
Scholarly Works, Biomedical Engineering and Mechanics
Scholarly Works, Fralin Biomedical Research Institute at VTC