Ephaptic Coupling Is a Mechanism of Conduction Reserve During Reduced Gap Junction Coupling.
Ephaptic Coupling Is a Mechanism of Conduction Reserve During Reduced Gap Junction Coupling.
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DOI：
10.3389/fphys.2022.848019
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发表时间：
2022
影响因子：
4
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中科院分区：
文献类型：
--
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许多心脏病理与减少的间隙连接（GJ）耦合，心脏传导速度（CV）的一个重要的调制器。然而，连接蛋白GJ家族蛋白的表型和功能表达之间的关系存在争议。例如，由于传导储备的概念，GJ耦合减少50%对心肌CV的影响很小。这可以通过突触耦合（EpC）理论来解释，其中传导通过低GJ耦合和在相邻肌细胞之间的钠通道富集裂隙中产生的增加的电场的组合来维持。同时，低GJ偶联也可能增加肌细胞内的细胞内电荷积累，导致去极化期间更快的跨膜电位变化率（dV/dt_max），其维持宏观传导。为了深入了解这两种现象在病理条件下的患病率，我们使用多细胞模拟和伴侣灌注小鼠心脏实验研究了在GJ重塑的背景下EpC和电荷积累之间的关系。传导沿着心肌细胞的纤维被模拟为一系列的GJ条件。该模型纳入了细胞间的变化，包括GJ耦合电导和分布，细胞间的分离，在闰盘（perinexal宽度-WP），和钠通道分布的变化。使用野生型小鼠和连接蛋白基因Gja 1的杂合无效小鼠进行具有与模拟条件类似的条件的灌注心脏研究。从模拟的洞察力，EpC和电荷积累的动作电位参数和传导速度的相对贡献进行了分析。模拟和实验结果都支持一个共同的结论，即低GJ耦合减少和缩小WP增加的AP upstroke的速率时，钠通道密集表达在肌细胞的末端，表明传导储备更依赖于EpC比电荷积累在GJ解偶联。
Many 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—WP), 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 WP 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.
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影响因子：
4
作者：
Entz M 2nd;George SA;Zeitz MJ;Raisch T;Smyth JW;Poelzing S
通讯作者：
Poelzing S
影响因子：
8.4
作者：
Dhillon，Paramdeep S.;Gray，Rosaire;Peters，Nicholas S.
通讯作者：
Peters，Nicholas S.
影响因子：
--
作者：
JALIFE, J;SICOURI, S;MICHAELS, DC
通讯作者：
MICHAELS, DC
影响因子：
20.1
作者：
BALKE, CW;LESH, MD;MOORE, EN
通讯作者：
MOORE, EN
影响因子：
5
作者：
Boyle, Patrick M.;Franceschi, William H.;Vigmond, Edward J.
通讯作者：
Vigmond, Edward J.