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

Abstract

It 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 GJ-mediated 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 and was 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-014-1675-z) contains supplementary material, which is available to authorized users.

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

“…In particular a population of Nav1.5 is located at the periphery of gap junctions in a so-called perinexus region that has been proposed to be involved in ephaptic conduction. 102 It might be possible that constitutive deletion of SAP97 led to compensatory modifications in the expression and/or organization of one more partner proteins that contributed to maintain Na V 1.5 expression.…”

Microstructure, Cell-to-Cell Coupling, and Ion Currents as Determinants of Electrical Propagation and Arrhythmogenesis

“…Experiments using genetically engineered ventricular and atrial mouse myocytes suggest that about 50% of Na v 1.5 channels are located in the intercalated disc, [66][67][68][69][70] whereby a fraction of these channels resides in close vicinity of gap junction plaques, the so-called perinexus. Early work by N. Sperelakis and more recent computer simulations [71][72][73][74][75] suggested that these channels may contribute the cell-to-cell transfer of cardiac impulses in presence of limited or in absence of cell-to-cell coupling by gap junctions. 76 Currently, experiments carried out at the cellular level are needed to provide an answer to this interesting hypothesis.…”

Molecular Mechanisms of Brugada Syndome Subtype 1

“…Однако позднее была показана колокализация Na v 1.5 с щелевыми контактами во вставочных дисках [22]. В действи-тельности макромолекуляный комплекс коннексо-на находится в тесном взаимодействии с натрие-выми каналами и десмосомами [23][24][25][26][27][28][29]. Морфоло-гические исследования подтверждают идею о том, что компоненты макромолекулярного комплекса коннексонов взаимодействуют между собой, а у пациентов с синдромом Бругада отмечается умень-шение количества щелевых контактов и увеличе-ние количества фиброзных структур с отложением коллагена в выходящем тракте правого желудочка [30,31].…”