电压门控钠离子通道疾病的研究进展

细胞膜上的电压门控钠离子通道（Voltage-gated Sodium Channels,VGSCs）是细胞形成动作电位过程中重要的组成构件,由一个大的α亚基和一个或多个不同的β亚基组成,中央是具高度选择性只允许钠离子通过的亲水通道。电压门控钠离子通道在调节细胞膜电位、维持细胞离子稳态、细胞增殖和凋亡等生理过程中发挥着重要作用,因而钠离子通道自身的异变或是相关基因的变异都可能引起一系列身体病变。本文主要介绍了电压门控钠离子通道的结构与功能,阐述了其与癌细胞侵袭转移和神经病理性疼痛的关系,并介绍了几种典型的由钠离子通道基因变异引起的疾病。随着对电压门控钠离子通道及其异常分子机制研究的不断深入,新成果将为生理学、药理学和病理学等领域的研究提供理论基础和新的研究思路,为离子通道疾病的临床预防、诊断与治疗找到新途径。     

电压门控钠通道的变异与机体疾患

通道病理学是当今国际学术发展中一门新兴学科。本文将针对有关电压门控钠通道的变异所导致的机体疾患,如高血钾性周期性麻痹,先天性肌强直等骨骼肌疾患,ＬＱＴ３,原发笥心室纤颤等心脏病及其所涉及的钠通道突变体,通道的突变位点和电生理性质等一些研究资料与进展作一概括介绍。     

电压门控钠通道NaV1.7与痛信号的产生

电压门控钠通道NaV1.7选择性高表达在伤害感受性脊髓背根神经节的感觉神经元上,在疼痛电信号的产生、传导和调控中具有重要的生理功能。伤害性感受器上的NaV1.7亦在慢性神经痛和炎症痛的病理生理过程中发挥关键作用。近年来的研究发现,人类遗传性疼痛症(如红斑性肢痛病)与NaV1.7钠离子通道基因SCN9A的某些功能增强型突变相关。最近Cox等首次报道了SCN9A突变将导致人先天痛觉完全丧失,而无痛症患者机体其它功能正常,提示NaV1.7将可能成为有效治疗疼痛而无副作用的一个新靶标。     

电压门控Na^＋通道亚型及其功能——新的研究热点

依靠现代分子生物学技术及电生理的记录,探讨各种Ｎａ＾＋通道亚型在中枢与周边神经系统以及一些非兴奋性组织细胞中的分布,表达,突变及其对信息调控的功能特征,已成为当今神经生物学等学科发展中的一个研究新热点,本文将侧重对有关哺乳动物Ｎａ＾＋通道亚型的分类,在不同组织细胞中的分布及其表达调控的功能机制等一些研究进展做一简要的回眸。     

电压门控钠通道与背根神经元伤害性传入

背根神经节（ＤＲＧ）神经元伤害性传入涉及到多层面复杂的神经递质与其相关靶受体的分子参与和调控。本文侧重结合ＤＲＧ神经元中钠电流的表达分布规律,简要地论及了电压门控钠通道与ＤＲＧ神经元伤害性性感觉传入及其调制的一些关系。     

电压门控钠通道结构与功能的适应性进化

电压门控钠通道是细胞兴奋性的重要分子基础,在进化演变中远早于神经元。伴随从细菌到脊椎动物的适应性演变,电压门控钠通道逐渐呈现出复杂的结构、功能和亚型多样性,且与诸多人类疾病密切相关。明确电压门控钠通道时空演变的适应性进化,解析电压门控钠通道的功能和结构多样性与人类重大疾病发生机制的相关性,有助于推进电压门控钠通道靶向临床诊疗新策略和新药的发现。     

电压门控钠离子通道与疼痛症

疼痛是一种常见的疾病和临床症状,有时会严重影响患者的生活质量,因此,疼痛的研究、治疗具有重要的实际意义。电压门控钠离子通道在神经元动作电位的起始和传导中起着关键作用,尤其是亚型Nav1.3、Nav1.7、Nav1.8和Nav1.9,它们广泛存在于背根神经节中,参与了疼痛的形成。其中,Nav1.7的基因突变会导致多种遗传性疾病。因此,这些亚型是潜在的、理想的疼痛治疗靶点。主要对电压门控钠离子通道与疼痛有关的最新研究进展进行了综述。     

电压门控性钾通道的结构和调控机制

电压门控性K 通道是由4个相同亚单位构成的四聚体通道,其中每个亚单位都含有1个电压感受器,并且4个亚单位合起来组成1个中央孔.电压门控性通道蛋白具有3种主要功能,一是离子通透功能,二是门控蛋白构象改变,三是门控与感知机制的偶联.通道具有高通透速率和高选择性,通过构象改变的门控机制有3种,一是S6束交叉门控,二是球链门控,三是选择性滤器的门控.     

神经病理性痛的交感-感觉耦联作用

周围组织和神经受到损伤引起自发性疼痛、触刺激诱发痛和痛觉过敏等慢性痛症状。交感神经系统通过发展异常交感功能,或者通过影响传入神经异常活动参与上述的病理性变化,进而造成神经病理性痛。本文对目前关于交感－感觉耦联作用及其受体、细胞内和神经机制进行综述。     

电压门控钠离子通道与恶性肿瘤的转移

电压门控钠离子通道(VGSC)是可兴奋组织中动作电位的关键离子通道,具有重要的生理功能.近年来国内外研究发现,VGSC在转移的前列腺癌、乳腺癌、卵巢癌、宫颈癌等细胞中表达,其增加了癌细胞的运动和侵袭,促使了癌症的转移,其还将被作为治疗靶点而进行药物开发和临床应用.     

Slow inactivation in voltage-gated sodium channels

Slow inactivation in voltage-gated sodium channels is a biophysical process that governs the availability of sodium channels over extended periods of time. Slow inactivation, therefore, plays an important role in controlling membrane excitability, firing properties, and spike frequency adaptation. Defective slow inactivation is associated with several diseases of cell excitability, such as hyperkalemic periodic paralysis, myotonia, idiopathic ventricular fibrillation and long-QT syndrome. These associations underscore the physiological importance of this phenomenon. Nevertheless, our understanding of the molecular substrates for slow inactivation is still fragmentary. This review covers the current state of knowledge concerning the molecular underpinnings of slow inactivation, and its relationship with other biophysical processes of voltage-gated sodium channels.     

Conotoxin modulation of voltage-gated sodium channels

The rising phase of the action potential in excitable cells is mediated by voltage-gated sodium channels (VGSCs), of which there are nine mammalian subtypes with distinct tissue distribution and biophysical properties. The involvement of certain VGSC subtypes in disease states such as pain and epilepsy highlights the need for agents that modulate VGSCs in a subtype-specific manner. Conotoxins from marine snails of the Conus genus constitute a promising source of such modulators, since these peptide toxins have evolved to become selective for various membrane receptors, ion channels and transporters in excitable cells. This review covers the structure and function of three classes of conopeptides that modulate VGSCs: the pore-blocking mu-conotoxins, the delta-conotoxins which delay or inhibit VGSC inactivation, and the muO-conotoxins which inhibit VGSC Na(+) conductance independent of the tetrodotoxin binding site. Some of these toxins have potential therapeutic and research applications, in particular the muO-conotoxins, which may develop into potential drug leads for the treatment of pain states.     

Excitability constraints on voltage-gated sodium channels

We study how functional constraints bound and shape evolution through an analysis of mammalian voltage-gated sodium channels. The primary function of sodium channels is to allow the propagation of action potentials. Since Hodgkin and Huxley, mathematical models have suggested that sodium channel properties need to be tightly constrained for an action potential to propagate. There are nine mammalian genes encoding voltage-gated sodium channels, many of which are more than approximately 90% identical by sequence. This sequence similarity presumably corresponds to similarity of function, consistent with the idea that these properties must be tightly constrained. However, the multiplicity of genes encoding sodium channels raises the question: why are there so many? We demonstrate that the simplest theoretical constraints bounding sodium channel diversity--the requirements of membrane excitability and the uniqueness of the resting potential--act directly on constraining sodium channel properties. We compare the predicted constraints with functional data on mammalian sodium channel properties collected from the literature, including 172 different sets of measurements from 40 publications, wild-type and mutant, under a variety of conditions. The data from all channel types, including mutants, obeys the excitability constraint; on the other hand, channels expressed in muscle tend to obey the constraint of a unique resting potential, while channels expressed in neuronal tissue do not. The excitability properties alone distinguish the nine sodium channels into four different groups that are consistent with phylogenetic analysis. Our calculations suggest interpretations for the functional differences between these groups.     

A superfamily of voltage-gated sodium channels in bacteria

NaChBac, a six-alpha-helical transmembrane-spanning protein cloned from Bacillus halodurans, is the first functionally characterized bacterial voltage-gated Na(+)-selective channel. As a highly expressing ion channel protein, NaChBac is an ideal candidate for high resolution structural determination and structure-function studies. The biological role of NaChBac, however, is still unknown. In this report, another 11 structurally related bacterial proteins are described. Two of these functionally expressed as voltage-dependent Na(+) channels (Na(V)PZ from Paracoccus zeaxanthinifaciens and Na(V)SP from Silicibacter pomeroyi). Na(V)PZ and Na(V)SP share approximately 40% amino acid sequence identity with NaChBac. When expressed in mammalian cell lines, both Na(V)PZ and Na(V)SP were Na(+)-selective and voltage-dependent. However, their kinetics and voltage dependence differ significantly. These single six-alpha-helical transmembrane-spanning subunits constitute a widely distributed superfamily (Na(V)Bac) of channels in bacteria, implying a fundamental prokaryotic function. The degree of sequence homology (22-54%) is optimal for future comparisons of Na(V)Bac structure and function of similarity and dissimilarity among Na(V)Bac proteins. Thus, the Na(V)Bac superfamily is fertile ground for crystallographic, electrophysiological, and microbiological studies.     

Molecular interaction of delta-conotoxins with voltage-gated sodium channels

Various neurotoxic peptides modulate voltage-gated sodium (Na(V)) channels and thereby affect cellular excitability. Delta-conotoxins from predatory cone snails slow down inactivation of Na(V) channels, but their interaction site and mechanism of channel modulation are unknown. Here, we show that delta-conotoxin SVIE from Conus striatus interacts with a conserved hydrophobic triad (YFV) in the domain-4 voltage sensor of Na(V) channels. This site overlaps with that of the scorpion alpha-toxin Lqh-2, but not with the alpha-like toxin Lqh-3 site. Delta-SVIE functionally competes with Lqh-2, but exhibits strong cooperativity with Lqh-3, presumably by synergistically trapping the voltage sensor in its "on" position.     

Molecular mechanisms of neurotoxin action on voltage-gated sodium channels

Voltage-gated sodium channels are the molecular targets for a broad range of neurotoxins that act at six or more distinct receptor sites on the channel protein. These toxins fall into three groups. Both hydrophilic low molecular mass toxins and larger polypeptide toxins physically block the pore and prevent sodium conductance. Alkaloid toxins and related lipid-soluble toxins alter voltage-dependent gating of sodium channels via an allosteric mechanism through binding to intramembranous receptor sites. In contrast, polypeptide toxins alter channel gating by voltage sensor trapping through binding to extracellular receptor sites. The results of recent studies that define the receptor sites and mechanisms of action of these diverse toxins are reviewed here.     

T型钙通道在神经病理性痛模型中介导疼痛的研究进展

神经病理痛是临床上常见病症,其发病机制尚不清楚,目前尚无有效的治疗手段,其慢性神经病理痛持续时间长,故其研究成为疼痛领域的热点和重点。近年来发现T型钙通道在神经病理性疼痛中起到了关键性的作用。本文将近年T型钙通道在神经病理性痛模型中介导疼痛的机制研究进展加以综述。