受体及离子通道蛋白磷酸化对跨膜信号传递的调节

跨膜信号转导是细胞信息传递的起始环节,受体和离子通道在此环节上起重要作用,受体和通道蛋白易受多种因素的调节。蛋白南磷酸化是受体及离子通道调节的关键步骤,不仅使受体及离子通道的功能发生改变,而且地影响到其在细胞的分布状况。受体 子通道蛋白酸化过程及其调节机制对于分析细胞信号转导的过程及细胞功能有着重要的作用。     

脆性X综合征FMRP缺失对离子通道的异常调控

脆性X综合征(FXS)由脆性X智力低下蛋白FMRP表达降低甚至完全缺失引起,是最常见的遗传性智力缺陷综合征和孤独症谱系障碍的单基因致病因素。FMRP不仅可与离子通道mRNA结合,如电压门控钾通道(Kv3.1和Kv4.2)等,还直接与多个离子通道作用,如钠激活钾通道(Slack)等。FMRP的缺失导致神经元离子通道表达异常和功能失调,在不同的脑区和不同的神经细胞类型中引起特定的离子稳态失衡、膜电位改变和兴奋性失常,导致神经环路过度兴奋。现就FMRP缺失对不同离子通道的异常调控及其研究进展进行综述。     

可兴奋细胞膜离子通道结构与功能的研究

生物膜离子通道结构与功能关系是当前多学科协同研究的一个“热点”。本文简述了研究的发展进程和主要方法技术,概述了离子通道主要类型的功能特征,包括宏观和单离子通道的电学特性、通道活化和失活动力学特征、药物对通道的激活与阻断作用等。进而从分子水平介绍了当前对一些通道蛋白分子构象与门控过程的研究进展。     

溶酶体离子通道蛋白在神经退行性疾病发生发展中的作用及机制研究

溶酶体离子通道蛋白异常引起溶酶体功能障碍是导致阿尔茨海默病(Alzheimer’s disease,AD)和帕金森病(Parkinson’s disease,PD)等神经退行性疾病的重要因素.溶酶体离子通道蛋白调节溶酶体内离子稳态、溶酶体膜电压以及溶酶体的酸度.溶酶体离子通道蛋白的结构或功能缺陷会引起溶酶体降解功能障碍,导致神经退行性疾病的发生发展.在这篇综述中,我们总结了各种离子通道蛋白调节溶酶体功能的过程及机制,以及离子通道蛋白异常参与神经退行性疾病的过程和机制.调节离子通道蛋白改善溶酶体的功能、促进异常聚集蛋白的清除,是神经退行性疾病治疗的潜在途径.     

肺上皮跨膜离子通道与急性肺损伤/急性呼吸窘迫综合征关系研究进展

急性肺损伤/急性呼吸窘迫综合征是临床上常见的并发症,以肺水肿和过度的炎症反应为主要特征。急性肺损伤/急性呼吸窘迫综合征往往伴随着肺离子通道功能受损,而修复这些离子通道功能能缓解其临床进展。因此了解上皮钠通道、钠钾泵、囊性纤维跨膜转导调节因子和水通道蛋白等通道功能及其与急性肺损伤/急性呼吸窘迫综合征相互关系对更好治疗此类疾病有重要意义。     

结核分枝杆菌感染对人巨噬细胞离子通道及其调控元件转录表达的影响

为研究人巨噬细胞的离子通道及其调控元件是否参与了抗结核分枝杆菌感染免疫,利用表达谱芯片技术研究细菌感染后主巨噬细胞基因的表达情况,在全局表达谱分析的基础上,重点分析了离子通道及其调控元件的表达,并比较无毒株和临床分离有毒株在诱导离子通道及其调控元件表达方面的差异。结果表明,细菌感染影响离子通道及其调控元件基因的表达,涉及的离子通道包括钾通道、钠通道、氯通道、钙通道,差异表达的调控元件包括G蛋白、G蛋白偶联受体、蛋白质激酶和磷酸化酶;临床株感染影响的离子通道及其调控元件较无毒株广泛和丰富。这些观察结果提示,离子通道及其调控元件参与了宿主细胞对感染细菌的免疫应答,有关离子通道及其调控元件在抗结核免疫中的作用有待进一步研究。芯片研究的结果为将来的研究提供了线索。     

离子通道亚型与其基因共表达的关联研究

离子通道亚型与其基因共表达的关联对研究离子通道功能有重要意义。文章采用主成分分析和模糊C-均值聚类算法对数据进行分析, 将方法应用到人类和小鼠两套表达谱数据, 结果发现离子通道亚型中钾离子通道、钙离子通道、氯离子通道和受体激活型离子通道的表达谱聚类结果与生物学分类有较好的一致性, 体现了离子通道亚型在mRNA水平上的共表达, 并证实了通过离子通道表达谱能很好的对离子通道的功能亚型进行分类。     

对"Channelopathy"定义及分类的一些看法

“Ｃｈａｎｎｅｌｏｐａｔｈｙ” ,又称“ＩｏｎｉｃＣｈａｎｎｅｌｏｐａｔｈｙ”。对于“Ｃｈａｎｎｅｌｏｐａｔｈｙ”的中译名目前多为“离子通道病” ,也有译为“通道病理学” ,前者基本上得到了普遍公认 ,并无太多异议。然而对于“离子通道病”的定义及分类目前还无明确概念 ,存在较多混淆。现一般多将“离子通道病”定义为“神经元或肌细胞膜上阳离子Ｎａ+、Ｋ+、Ｃａ2 +通道和阴离子Ｃｌ- 通道由于编码通道蛋白的基因发生突变导致通道功能和 (或 )结构异常的一类疾病”。笔者认为这一定义存在较大缺陷 ,其缺点在于 :(1)过于片面 ;(2…     

环核苷酸门控离子通道的结构、功能及活性调节

环核苷酸门控离子通道（cyclic nucleotide-gated ion channels,CNG）是非选择性的阳离子通道,直接被环核苷酸活化.6个不同基因编码CNG离子通道蛋白,4个A亚单元(A1～A4)和2个B亚单元(B1,B3).CNG离子通道是由2个或3个不同的亚单元组成的异四聚体复合物,是Ca2+进入细胞内的主要通道之一.CNG离子通道的活性可被Ca2+ /CaM及磷酸化/去磷酸化作用所调节,从而改变细胞内钙离子浓度,触发一系列生理效应.近年来CNG离子通道的研究进展神速,成为生命科学的一个热点领域.本文对CNG离子通道的结构、功能及活性调节机制进行了综述.     

离子通道蛋白在溃疡性结肠炎腹泻中的作用及调控机制

溃疡性结肠炎(UC)是炎症性肠病(IBD)的一种,主要临床表现为迁延不愈的腹泻及便血。离子通道蛋白的表达和活性降低引起的肠腔水、电解质潴留是造成UC腹泻的主要原因。近年来,关于离子通道蛋白的功能及其调控机制的研究取得了突破性的进展:一方面,掌握了炎症因子调控离子通道蛋白表达的确切证据;另一方面,明确了UC中离子通道蛋白与肠道菌群的相互作用机制。现就上述进展做一综述,为发展新的UC治疗方法提供有用证据。     

Regulation of epithelial ion channels by Rab GTPases

Epithelial ion channels are crucial to many of life's processes and disruption of their functions can lead to several disorders. Cystic fibrosis, an autosomal recessive disorder, is caused by defects in the biosynthesis or function of the CFTR chloride channel. Similarly, mutations in certain ENaC genes leading to increased or reduced channel activity cause diseases such as Liddle's syndrome or PHA. In order for ion channel proteins to be functional they need to be expressed on the plasma membrane. Thus, molecules that modulate the trafficking of ion channels to and from the membrane are of utmost significance. Among the numerous factors that regulate their functioning is a family of small GTPases known as Rab proteins. While Rabs have always played a pivotal role in membrane trafficking, their diversity of functions and plethora of interacting partners have lately been brought to light. Recent studies reveal that multiple Rab isoforms physically interact with and/or modulate the activity of several ion channels. Rab proteins have the ability to serve as molecular switches and many of the ion channels are regulated differentially by the GTP- or GDP-bound Rab isoforms. This review examines the role of Rab GTPases in the trafficking of ion channels, including CFTR, ENaC, TRPV5/6, and aquaporins, based on recent evidence.     

Transporters of Neurotransmitters: Receptive, Transport, and Channel Functions

Based on possible unity of the evolutionary origin of some prokaryotic proteins with eukaryotic ion channels and receptors, this review analyzes interconnections between receptive, transport, and channel functions of integral proteins. This interconnection can be considered the best by the example of neurotransmitter transporters. Their role in chemical synapses and their possible participation in phenomena of synaptic plasticity are reviewed. There are discussed mechanisms of transporter functioning, such as the allosteric model and the model of activity by the principle of channel, as well as data about coupling by the transporters of reception of substrate and its transport with the substrate-activated channel of Cl^–-conductance and the ion leakage. The importance of the latter aspects of the neurotransmitter transporter functioning is usually underestimated in studying neuronal and glial electrogenesis.     

检测钾离子通道的小分子荧光探针的研究进展

钾离子通道是分布最为广泛、种类繁多的一类离子通道,因其生理功能的多样性,已成为许多疾病的药物作用靶点。近年来,许 多化学结构不同的药物均因钾离子通道阻滞引起的严重心肌毒性而被撤出市场,使得小分子药物的钾通道抑制活性筛选面临重大挑战。 介绍检测钾离子通道的小分子荧光探针的研究进展,并总结小分子荧光探针的作用机制,为今后小分子荧光探针的设计提供思路,使得 小分子荧光探针可以广泛应用于候选药物的高通量筛选、钾离子通道的活体成像与检测。     

Ca2+ modulation of Ca2+ release-activated Ca2+ channels is responsible for the inactivation of its monovalent cation current

The Ca(2+) release-activated Ca(2+) (CRAC) channel is the most well documented of the store-operated ion channels that are widely expressed and are involved in many important biological processes. However, the regulation of the CRAC channel by intracellular or extracellular messengers as well as its molecular identity is largely unknown. Specifically, in the absence of extracellular divalent cations it becomes permeable to monovalent cations with a larger conductance, however this monovalent cation current inactivates rapidly by an unknown mechanism. Here we found that Ca(2+) dissociation from a site on the extracellular side of the CRAC channel is responsible for the inactivation of its Na(+) current, and Ca(2+) occupancy of this site otherwise potentiates its Ca(2+) as well as Na(+) currents. This Ca(2+)-dependent potentiation is required for the normal functioning of CRAC channels.     

Mutational analysis of ABC proteins

The 49 human members of the ATP-binding cassette (ABC) family of proteins are involved in a wide range of activities such as active transport of compounds across membranes, extraction of compounds out of membranes, functioning as ion channels, or regulators of channel activity. Mutations and/or overexpression of many of the proteins can have adverse effects on health. A goal in the study of ABC proteins is to understand their mechanisms of action. This review will focus on the mutational approaches that have been used to study the structure and mechanisms of some ABC proteins.     

Recent advances in the characterization of epithelial ionic channels

Physiologists have long recognized the importance of channels in the functioning of neurons and excitable membranes. This brief review has been an attempt to illustrate how channel properties are also essential to an understanding of epithelial transport physiology. Among their more important functions, channels influence membrane potentials and serve as conduits for ion movements. As the need to understand the molecular basis for ion transport continues to develop, it is crucial to be able to distinguish between different channel properties. For example, apparent voltage-dependent properties can arise because of a voltage-dependent gating process, or alternatively, because of a rectification of channel conductance. Voltage-dependent effects can also be only indirect, mediated by changes in cell volume, intracellular ion levels, the levels of secondary intracellular messengers such as Ca2+ (perhaps through voltage-dependent membrane Ca2+ channels), or possibly even by morphological changes. An important area for future research is to differentiate mechanisms which modulate the activity of open channels. For example, a decrease in channel number, a reduction in open-channel conductance or a decline in the probability of channel opening can all underlie changes in macroscopic permeability. The factors which mediate hormonal activation of epithelial channels particularly need to be understood. Specifically, the mechanisms of aldosterone and anti-diuretic hormone activation of apical membrane Na+ channels need to be identified. In conclusion, we are witnessing a new era in epithelial electrophysiology which promises to resolve many issues concerning the cellular regulation of ion transport and open new, unanticipated avenues of inquiry.     

大电导钾离子通道(BK)结构与功能的研究进展

大电导钙离子激活钾通道(BK)是细胞膜上唯一接受细胞内Ca2+和膜电位双重调控的离子通道.最新发表的关于BK通道电镜结构及其胞质功能域的晶体结构的文章,第一次展示了BK通道各亚基的组装,并证实通道各功能域在通道门控机制中存在紧密的相互作用.近年来,针对BK通道的功能调节及其门控动力学模拟的研究取得较多进展,有助于更好地理解BK通道发挥生理功能的门控机制,并揭示BK通道相关疾病的病理生理学基础.     

Cardiac channelopathies: Genetic and molecular mechanisms

Channelopathies are diseases caused by dysfunctional ion channels, due to either genetic or acquired pathological factors. Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since seminal observations made in 1995, thousands of mutations have been found in many of the different genes that code for cardiac ion channel subunits and proteins that regulate the cardiac ion channels. The main phenotypes observed in patients carrying these mutations are congenital long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS) and variable types of conduction defects (CD). The goal of this review is to present an update of the main genetic and molecular mechanisms, as well as the associated phenotypes of cardiac channelopathies as of 2012.     

Nuclear magnetic resonance structural studies of a potassium channel-charybdotoxin complex

Ion channels play critical roles in signaling processes and are attractive targets for treating various diseases. Here we describe an NMR-based strategy for structural analyses of potassium channel-ligand complexes using KcsA (residues 1-132, with six mutations to impart toxin binding and to mimic the eukaryotic hERG channel). Using this approach, we determined the solution structure of KcsA in complex with the high-affinity peptide antagonist charybdotoxin. The structural data reveal how charybdotoxin binds to the closed form of KcsA and makes specific contacts with the extracellular surface of the ion channel, resulting in pore blockage. This represents the first direct structural information about an ion channel complexed to a peptide antagonist and provides an experimental framework for understanding and interpreting earlier mutational analyses. The strategy presented here overcomes many of the limitations of conventional NMR approaches to helical membrane protein structure determination and can be applied in the study of the binding of druglike molecules to this important class of proteins.     

Diseases caused by voltage-gated ion channels

Ion channels regulate the transfer of ions between the outer and the inner surface of the cell membrane. The opening of ion channels may be triggered by the binding of a ligand or variations in the membrane potential. Voltage-gated ion channels are an important class of such channels, that are involved in the generation and propagation of action potentials and play a key role in cell to cell communication. As a consequence of cloning and sequencing of ion channel genes, their role in diseases affecting excitable tissues such as the nervous system, heart and skeletal muscle has been examined, and a new class of diseases has emerged. We will review disorders caused by mutations in voltage-gated ion channels affecting these excitable tissues as well as non-excitable tissues such as the kidney. The clinician should be aware of this new class of diseases because pharmacological agents modulating channel functions are available. Characterization of these gene defects should lead to better treatment of these disorders.