Localization of Na⁺ channel clusters in narrowed perinexi of gap junctions enhances cardiac impulse transmission via ephaptic coupling: a model study

Abstract

This is the MATLAB source code permitting to replicate the simulations presented in an article that is presently under peer-review for publication. Download all files into the same folder. Details regarding the operation of the scripts and functions are presented briefly below and in detail as comments at the beginning of the scripts/functions as well as throughout the code. These simulations are optimally run in MATLAB version 2019a on a PC with the Windows 10 operating system, an Intel Core i7 processor and 64 GB of RAM.Use in terms of the Creative Commons CC-BY license (Attribution 4.0 International) and, regarding the functions from the "DistMesh" package (see below), under the terms of the GNU General Public License version 2.

Nano-scale solution of the Poisson-Nernst-Planck (PNP) equations in a fraction of two neighboring cells reveals the magnitude of intercellular electrochemical waves

“…Therefore, we conclude that the number of Na + channels rather than the cluster size is the key factor in our simulation results. Moreover, the reduction of the extracellular cleft width (from 30 nm to 5 nm), leading to more negative extracellular potentials in the cleft is consistent with previously published computational studies at the cellular level [9, 21, 3]. With decreasing cleft width, negative extracellular potentials in the local neighborhood of the Na + channel cluster of the left cell are transmitted to the other side of the cleft (close to the right cell), where it is likely to affect Na + channel gating, thus forming the basis for ephaptic coupling.…”

“…An alternative route of conduction from cell to cell is via the extracellular space, referred to as ephaptic coupling. This alternative has been discussed for a very long time (see, e.g., [18, 19]) and recent modeling results, emphasizing the importance of the localization of the ion channels, indicate that ephaptic coupling is a viable alternative way of conduction, see, e.g., [20, 21, 3, 22]. A related discussion goes on in computational neurophysiology where the question is whether or not a neuron can set off an excitation wave in a neighboring cell; see [23, 24, 25, 26, 27].…”

Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts

“…These defects were also associated with a widening of perinexus intermembrane distance with changes in non-perinexal distances, a phenomenon that has been linked to arrhythmogenic conduction defects 4 . Impaired conduction could further originate from changes in ICD and perinexal nanodomain structure 39 – 42 which can modulate interplay between Cx43-dependent gap junctions and trans-sarcolemmal ion fluxes, and further strongly influence the localized transmembrane voltages and thereby NaV1.5 function 36 , 38 . Indeed, since we observed no I Na changes between Tmem65 KD hearts and control cardiomyocytes, it would seem reasonable to suggest that any effects of I Na on slowed conduction in Tmem65 KD hearts would be secondary to changes in the ICD.…”

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

“…Other numerical models of varying complexity that incorporated the 3D geometry of the intracellular and extracellular space have also shown that EpC plays an important role in CV ( Kucera et al, 2002 ; Stinstra et al, 2005 ; Mori et al, 2007 ; Mori et al, 2008 ; Roberts et al, 2008 ; Ivanovic and Kucera, 2021 ; Moise et al, 2021 ). While our choice of numerical model may dictate the simulated CV values, the important features we have elucidated here will match other detailed models in the trends.…”