Morris Joshua A, Bardsley Oliver J, Salvage Samantha C, Jackson Antony P, Matthews Hugh R, Huang Christopher L-H
Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom.
Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
Front Physiol. 2024 Jan 3;14:1280151. doi: 10.3389/fphys.2023.1280151. eCollection 2023.
In addition to gap junction conduction, recent reports implicate possible ephaptic coupling contributions to action potential (AP) propagation between successive adjacent cardiomyocytes. Here, AP generation in an active cell, withdraws Na from, creating a negative potential within, ephaptic spaces between the participating membranes, the initially quiescent neighbouring cardiomyocyte. However, sustainable ephaptic transmission requires subsequent complete of the ephaptic charge difference. We explore physical contributions of passive electrodiffusive ion exchange with the remaining extracellular space to this recovery for the first time. Computational, finite element, analysis examined limiting, temporal and spatial, ephaptic [Na], [Cl], and the consequent Gaussian charge differences and membrane potential recovery patterns following a Δ∼130 mV AP upstroke at physiological (37°C) temperatures. This incorporated Nernst-Planck formalisms into equations for the time-dependent spatial concentration gradient profiles. Mammalian atrial, ventricular and purkinje cardiomyocyte ephaptic junctions were modelled by closely apposed circularly symmetric membranes, specific capacitance 1 μF cm, experimentally reported radii 8,000, 12,000 and 40,000 nm respectively and ephaptic axial distance = 20 nm. This enclosed an ephaptic space containing principal ions initially at normal extracellular [Na] = 153.1 mM and [Cl] = 145.8 mM, respective diffusion coefficients = 1.3 10 and = 2 10 nms. Stable, concordant computational solutions were confirmed exploring ≤1,600 nm mesh sizes and Δ≤0.08 ms stepsize intervals. The corresponding membrane voltage profile changes across the initially quiescent membrane were obtainable from computed, graphically represented and -dependent ionic concentration differences adapting Gauss's flux theorem. Further simulations explored biological variations in ephaptic dimensions, membrane anatomy, and diffusion restrictions within the ephaptic space. Atrial, ventricular and Purkinje cardiomyocytes gave 40, 180 and 2000 ms 99.9% recovery times, with 720 or 360 ms high limits from doubling ventricular radius or halving diffusion coefficient. Varying , and and markedly affected recovery time-courses with logarithmic and double-logarithmic relationships, Varying exerted minimal effects. We thereby characterise the properties of, and through comparing atrial, ventricular and purkinje recovery times with interspecies background cardiac cycle duration data, (blue whale ∼2000, human∼90, Etruscan shrew, ∼40 ms) can determine physical limits to, electrodiffusive contributions to ephaptic recovery.
除了缝隙连接传导外，最近的报告表明，可能存在电突触耦合对连续相邻心肌细胞之间动作电位（AP）传播的贡献。在这里，活跃细胞中产生的动作电位会从参与的细胞膜之间的电突触间隙中提取钠离子，从而在最初静止的相邻心肌细胞的电突触间隙内产生负电位。然而，可持续的电突触传递需要随后完全恢复电突触电荷差。我们首次探索了与剩余细胞外空间的被动电扩散离子交换对这种恢复的物理贡献。通过计算、有限元分析，研究了生理温度（37°C）下，动作电位上升约130 mV后，电突触中钠离子、氯离子的极限、时间和空间分布，以及由此产生的高斯电荷差和膜电位恢复模式。这将能斯特-普朗克形式体系纳入了随时间变化的空间浓度梯度分布方程。通过紧密并置的圆对称膜对哺乳动物心房、心室和浦肯野心肌细胞的电突触连接进行建模，比电容为1 μF/cm²，实验报道的半径分别为8000、12000和40000 nm，电突触轴向距离为20 nm。这包围了一个电突触空间，其中主要离子最初处于正常细胞外钠离子浓度153.1 mM和氯离子浓度145.8 mM，各自的扩散系数分别为1.3×10⁻⁹和2×10⁻⁹ m²/s。通过探索≤1600 nm的网格尺寸和Δ≤0.08 ms的步长间隔，证实了稳定、一致的计算解。根据计算得出的、图形表示的以及依赖于离子浓度差的膜电压分布变化，采用高斯通量定理可得到最初静止膜上相应的膜电压分布变化。进一步的模拟研究了电突触尺寸、膜解剖结构以及电突触空间内扩散限制的生物学变化。心房、心室和浦肯野心肌细胞的99.9%恢复时间分别为40、180和2000 ms，心室半径加倍或扩散系数减半会使恢复时间上限达到720或360 ms。改变钠离子、氯离子的扩散系数以及膜电容会显著影响恢复时间进程，呈现对数和双对数关系，改变轴向距离的影响最小。我们据此表征了电突触恢复的特性，并通过比较心房、心室和浦肯野细胞的恢复时间与种间背景心动周期持续时间数据（蓝鲸约2000 ms，人类约90 ms，伊特鲁里亚鼩鼱约40 ms），可以确定电扩散对电突触恢复贡献的物理极限。
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