Roles of Subcellular Na + Channel Distributions in the Mechanism of Cardiac Conduction

Abstract

The gap junction and voltage-gated Na(+) channel play an important role in the action potential propagation. The purpose of this study was to elucidate the roles of subcellular Na(+) channel distribution in action potential propagation. To achieve this, we constructed the myocardial strand model, which can calculate the current via intercellular cleft (electric-field mechanism) together with gap-junctional current (gap-junctional mechanism). We conducted simulations of action potential propagation in a myofiber model where cardiomyocytes were electrically coupled with gap junctions alone or with both the gap junctions and the electric field mechanism. Then we found that the action potential propagation was greatly affected by the subcellular distribution of Na(+) channels in the presence of the electric field mechanism. The presence of Na(+) channels in the lateral membrane was important to ensure the stability of propagation under conditions of reduced gap-junctional coupling. In the poorly coupled tissue with sufficient Na(+) channels in the lateral membrane, the slowing of action potential propagation resulted from the periodic and intermittent dysfunction of the electric field mechanism. The changes in the subcellular Na(+) channel distribution might be in part responsible for the homeostatic excitation propagation in the diseased heart.

The cardiac connexome: Non-canonical functions of connexin43 and their role in cardiac arrhythmias

“…This notion contrasts sharply with actual data showing that only extreme reductions in Cx43 abundance (and electrical coupling) lead to significant changes in conduction velocity [11, 57, 58]. These results have given new impetus to the notion that, under poor gap junction-mediated coupling, propagation can be maintained via a separate “electric field mechanism” [44, 45, 47, 52] also referred to as “ephaptic transmission” [9, 47, 52]. This alternative postulates that the large I Na in the proximal side of an intercellular cleft generates a negative extracellular potential within the cleft, which depolarizes the distal membrane and activates its sodium channels.…”

“…Rather, we propose that molecules of the intercalated disc multi-task within a protein interacting network (the connexome), working in concert toward one common function: the propagation of excitatory current from one cell to the next. From this perspective, Cx43 is a molecule relevant to cell excitability (by modulating I Na ) [29, 30], sodium channels can support cell-cell electrical coupling and intercellular adhesion strength [44, 45], and “adhesion molecules” are actually required for the function of electrical complexes [51, 59, 60]. The results have important consequences in translational medicine.…”

“…This view, however, is changing. Mathematical modeling studies (e.g., [44, 45]) and experimental evidence [46] support the idea that the intercellular space may be critical to propagation via an electric field mechanism [47]. This model will be discussed later in this review.…”

Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes

“…Yet, subcellular segregation may be critical under conditions where electrical coupling is decreased. 21 In fact, computer simulations of action potential propagation between cardiac cells 3,22 suggest that the increased I Na density at the ID may allow for field-mediated activation of the neighboring cell even in the absence of functional gap junctions. Further experimental and numerical studies, including accurate measurements of the volume of the intercellular gap, remain necessary to validate the latter hypothesis.…”

Intercellular Electrical Communication in the Heart: A New, Active Role for the Intercalated Disk

“…On the structural side, it has been demonstrated that Na v 1.5 channels are preferentially localized at the ID compared with the lateral membrane of cardiac myocytes and are trafficked to these membrane sub-domains via distinct pathways (Petitprez et al, 2011). Functionally, this translates into elevated sodium current density at the ID compared with the lateral membrane (Lin et al, 2011) and in silico results have gone as far as suggesting that disk-localized sodium channels may be primarily responsible for depolarization while those on the lateral membrane help maintain the stability of conduction (Tsumoto et al, 2011). …”