A single Markov-type kinetic model accounting for the macroscopic currents of all human voltage-gated sodium channel isoforms
A single Markov-type kinetic model accounting for the macroscopic currents of all human voltage-gated sodium channel isoforms
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DOI：
10.1371/journal.pcbi.1005737
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发表时间：
2017-09-01
影响因子：
4.3
通讯作者：
Kotaleskim, Jeanette Hellgren
中科院分区：
文献类型：
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作者：
Balbi, Pietro;Massobrio, Paolo;Kotaleskim, Jeanette Hellgren
离子通道建模代表了开发生物学详细神经元模型的基本步骤。直到最近，电压门控离子通道主要根据 Hodgkin 和 Huxley (HH) 的开创性著作引入的形式主义进行建模。然而，随着这些成孔跨膜蛋白的生物物理和分子理解不断取得成就，HH 形式主义在再现离子通道电生理行为方面存在局限性和不一致之处。与此同时，马尔可夫型动力学模型已被越来越多地证明可以成功复制不同离子通道的电生理学和生物物理特征。然而，为了模拟最精细的非导电分子构象变化，它们通常配备有相当数量的状态和相关转变，这使得它们计算量很大，不太适合在基于电导的神经元和大型网络中实现。在这项纯粹的建模研究中，我们为所有人类电压门控钠通道（VGSC）开发了马尔可夫型动力学模型。该模型框架详细、统一（即，它考虑了所有离子通道亚型）并且计算高效（即具有最小的状态和转换集）。要建模的电生理学数据收集自先前发表的关于异源表达人类 VGSC 亚型（从 Na(V)1.1 到 Na(V)1.9）的哺乳动物细胞系的全细胞膜片钳实验的研究。通过采用最小状态序列，并对所有不同的异构体使用相同的状态图，该模型确保在复杂性不断增加的神经元模型和神经网络中使用时计算负载最轻。状态之间的转变由原始常微分方程描述，该方程将状态转变速率表示为电压（即膜电位）的函数。在 NEURON 模拟环境中开发的动力学模型似乎是对人类 VGSC 电生理行为进行详细现象学描述的最简单、最简约的方法。
Modelling ionic channels represents a fundamental step towards developing biologically detailed neuron models. Until recently, the voltage-gated ion channels have been mainly modelled according to the formalism introduced by the seminal works of Hodgkin and Huxley (HH). However, following the continuing achievements in the biophysical and molecular comprehension of these pore-forming transmembrane proteins, the HH formalism turned out to carry limitations and inconsistencies in reproducing the ion-channels electrophysiological behaviour. At the same time, Markov-type kinetic models have been increasingly proven to successfully replicate both the electrophysiological and biophysical features of different ion channels. However, in order to model even the finest non-conducting molecular conformational change, they are often equipped with a considerable number of states and related transitions, which make them computationally heavy and less suitable for implementation in conductance-based neurons and large networks of those. In this purely modelling study we develop a Markov-type kinetic model for all human voltage-gated sodium channels (VGSCs). The model framework is detailed, unifying (i.e., it accounts for all ion-channel isoforms) and computationally efficient (i.e. with a minimal set of states and transitions). The electrophysiological data to be modelled are gathered from previously published studies on whole-cell patch-clamp experiments in mammalian cell lines heterologously expressing the human VGSC subtypes (from Na(V)1.1 to Na(V)1.9). By adopting a minimum sequence of states, and using the same state diagram for all the distinct isoforms, the model ensures the lightest computational load when used in neuron models and neural networks of increasing complexity. The transitions between the states are described by original ordinary differential equations, which represent the rate of the state transitions as a function of voltage (i.e., membrane potential). The kinetic model, developed in the NEURON simulation environment, appears to be the simplest and most parsimonious way for a detailed phenomenological description of the human VGSCs electrophysiological behaviour.