Zn2+-induced changes in Cav2.3 channel function: An electrophysiological and modeling study
Zn2+-induced changes in Cav2.3 channel function: An electrophysiological and modeling study
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DOI：
10.1085/jgp.202012585
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发表时间：
2020-09-01
影响因子：
3.8
通讯作者：
Schneider，Toni
中科院分区：
文献类型：
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作者：
Neumaier，Felix;Alpdogan，Serdar;Schneider，Toni
在正常和病理生理条件下，松散结合的Zn2+离子越来越被认为是突触可塑性和神经元兴奋性的潜在调节剂。Cav2.3电压门控Ca2+通道是Zn2+最敏感的靶点之一，因此可能参与内源性Zn2+的神经调节作用。虽然结构域I外部的组氨酸残基与Cav2.3通道门控的影响有关，但通道调制的确切机制仍不完全清楚。在这里，我们结合电生理记录、组氨酸残基修饰和计算模型来分析Zn2+诱导的Cav2.3通道功能的变化。我们最重要的发现是多种高亲和力和低亲和力机制有助于Zn2+的净作用，Zn2+可以抑制或刺激Ca2+通过Cav2.3通道依赖于静息膜电位，并且Zn2+的作用可能持续一段时间，甚至在Zn2+信号停止后。计算机模拟表明：(1)在没有微量金属的情况下，Cav2.3通道门控的最显著特征可以通过一个必须激活两个电压传感器才能打开孔的强制模型来重现；(2)大多数（但不是全部）Zn2+的影响可以通过假设Zn2+结合到第一个位点与静电修饰和其中一个电压传感器的机械减速有关，而Zn2+结合到第二个低亲和力位点阻断通道并改变打开和关闭转变来解释。虽然还远未完成，但我们的模型为理解Zn2+对Cav2.3通道函数的影响提供了第一个定量框架，并向应用计算方法预测Zn2+对神经元兴奋性的复杂作用迈出了一步。
Loosely bound Zn2+ions are increasingly recognized as potential modulators of synaptic plasticity and neuronal excitability under normal and pathophysiological conditions. Cav2.3 voltage-gated Ca2+channels are among the most sensitive targets of Zn2+and are therefore likely to be involved in the neuromodulatory actions of endogenous Zn2+. Although histidine residues on the external side of domain I have been implicated in the effects on Cav2.3 channel gating, the exact mechanisms involved in channel modulation remain incompletely understood. Here, we use a combination of electrophysiological recordings, modification of histidine residues, and computational modeling to analyze Zn2+-induced changes in Cav2.3 channel function. Our most important findings are that multiple high- and low-affinity mechanisms contribute to the net Zn2+action, that Zn2+can either inhibit or stimulate Ca2+influx through Cav2.3 channels depending on resting membrane potential, and that Zn2+effects may persist for some time even after cessation of the Zn2+signal. Computer simulations show that (1) most salient features of Cav2.3 channel gating in the absence of trace metals can be reproduced by an obligatory model in which activation of two voltage sensors is necessary to open the pore; and (2) most, but not all, of the effects of Zn2+can be accounted for by assuming that Zn2+binding to a first site is associated with an electrostatic modification and mechanical slowing of one of the voltage sensors, whereas Zn2+binding to a second, lower-affinity site blocks the channel and modifies the opening and closing transitions. While still far from complete, our model provides a first quantitative framework for understanding Zn2+effects on Cav2.3 channel function and a step toward the application of computational approaches for predicting the complex actions of Zn2+on neuronal excitability.