Lin Joyce, Abraham Anand, George Sharon A, Greer-Short Amara, Blair Grace A, Moreno Angel, Alber Bridget R, Kay Matthew W, Poelzing Steven
Department of Mathematics, California Polytechnic State University, San Luis Obispo, CA, United States.
Virginia Tech Carilion School of Medicine, Roanoke, VA, United States.
Front Physiol. 2022 May 5;13:848019. doi: 10.3389/fphys.2022.848019. eCollection 2022.
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 () 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), 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 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.
许多心脏疾病都与间隙连接（GJ）耦联减少有关，间隙连接是心脏传导速度（CV）的重要调节因子。然而，连接蛋白GJ家族蛋白的表型与功能表达之间的关系存在争议。例如，由于传导储备这一概念，GJ耦联减少50%已被证明对心肌CV影响很小。这可以通过电紧张耦联（EpC）理论来解释，即传导通过低GJ耦联和相邻心肌细胞间富含钠通道的裂隙中产生的电场增加的组合来维持。同时，低GJ耦联也可能增加心肌细胞内的电荷积累，导致去极化期间跨膜电位变化速率加快（），从而维持宏观传导。为了深入了解这两种现象在病理状态下的普遍性，我们使用多细胞模拟和配套的灌注小鼠心脏实验，研究了GJ重塑背景下EpC与电荷积累之间的关系。针对一系列GJ条件，模拟了心肌细胞纤维上的传导。该模型纳入了细胞间的差异，包括GJ耦联电导和分布、闰盘中细胞间的间距（周缘宽度-W）以及钠通道分布的变化。使用野生型小鼠和连接蛋白基因Gja1杂合缺失的小鼠进行了与模拟条件类似的灌注心脏研究。借助模拟结果分析了EpC和电荷积累对动作电位参数和传导速度的相对贡献。模拟和实验结果均支持一个共同结论，即当钠通道在心肌细胞末端密集表达时，低GJ耦联会降低，W变窄会增加动作电位上升速率，这表明在GJ解耦期间，传导储备更多地依赖于EpC而非电荷积累。
