Joos Bela, Barlow Benjamin M, Morris Catherine E
Department of Physics, University of Ottawa, Ottawa, ON, Canada.
Neurosciences, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Handb Exp Pharmacol. 2018;246:401-422. doi: 10.1007/164_2017_63.
Two features common to diverse sick excitable cells are "leaky" Nav channels and bleb damage-damaged membranes. The bleb damage, we have argued, causes a channel kinetics based "leakiness." Recombinant (node of Ranvier type) Nav1.6 channels voltage-clamped in mechanically-blebbed cell-attached patches undergo a damage intensity dependent kinetic change. Specifically, they experience a coupled hyperpolarizing (left) shift of the activation and inactivation processes. The biophysical observations on Nav1.6 currents formed the basis of Nav-Coupled Left Shift (Nav-CLS) theory. Node of Ranvier excitability can be modeled with Nav-CLS imposed at varying LS intensities and with varying fractions of total nodal membrane affected. Mild damage from which sick excitable cells might recover is of most interest pathologically. Accordingly, Na/K ATPase (pump) activity was included in the modeling. As we described more fully in our other recent reviews, Nav-CLS in nodes with pumps proves sufficient to predict many of the pathological excitability phenomena reported for sick excitable cells. This review explains how the model came about and outlines how we have used it. Briefly, we direct the reader to studies in which Nav-CLS is being implemented in larger scale models of damaged excitable tissue. For those who might find it useful for teaching or research purposes, we coded the Nav-CLS/node of Ranvier model (with pumps) in NEURON. We include, here, the resulting "Regimes" plot of classes of excitability dysfunction.
多种患病的可兴奋细胞共有的两个特征是“渗漏性”钠通道和泡状损伤——受损的细胞膜。我们认为，泡状损伤会导致基于通道动力学的“渗漏性”。在机械形成泡状的细胞贴附膜片钳中进行电压钳制的重组（郎飞结型）Nav1.6通道会经历依赖于损伤强度的动力学变化。具体而言，它们的激活和失活过程会发生耦合的超极化（向左）移位。关于Nav1.6电流的生物物理观察结果构成了Nav耦合左移（Nav-CLS）理论的基础。郎飞结兴奋性可以通过在不同的左移强度下施加Nav-CLS以及不同比例的总结间膜受到影响来进行建模。患病的可兴奋细胞可能从中恢复的轻度损伤在病理学上最受关注。因此，钠钾ATP酶（泵）活性被纳入建模。正如我们在近期的其他综述中更全面描述的那样，有泵的结中Nav-CLS足以预测报道的患病可兴奋细胞的许多病理兴奋性现象。这篇综述解释了该模型是如何产生的，并概述了我们如何使用它。简而言之，我们引导读者参考在受损可兴奋组织的大规模模型中实施Nav-CLS的研究。对于那些可能发现它对教学或研究有用的人，我们在NEURON中对Nav-CLS/郎飞结模型（有泵）进行了编码。在此，我们给出由此得到的兴奋性功能障碍类别的“状态”图。
