电压门控离子通道功能与结构分子模型

离子通道是细胞膜上特殊跨膜蛋白构成的亲水孔道,越来越多的证据表明其与兴奋性、腺体分泌、机体运动、甚至学习和记忆行为等重要生理现象密切相关,由此该领域成为当今生命学科广为注目的前沿之一。本文将简要介绍离子通道的分类和功能,并侧重阐明通道压控原理及压控通道的跨膜拓扑结构和功能分子模型。     

基于HMM的低信噪比离子通道信号的恢复及参数估计

细胞膜离子单通道信号是皮安级的随机电流 ,膜片钳技术可以记录这些信号。一般认为它是一阶的、状态有限的 Markov过程。某些种类的离子通道 ,电流信号特别微弱 ,完全淹没在背景噪声中 ,传统的膜片钳技术很难检测到 ,只能运用数学方法恢复和估计。在低采样频率情况下 ,由于混叠效应 ,可认为背景噪声是白色的 ;在高采样频率条件下 (高于奈奎斯特频率 ) ,背景噪声是有色的。本文分别综述了白色背景噪声条件下基于隐式 Markov模型和有色背景噪声条件下基于隐式矢量 Markov模型的低信噪比离子单通道信号的恢复和参数估计 ,主要包括前后向算法、EM算法等     

进化策略,进化规划在医用非线性曲线拟合中的应用

作者提出医用非线性曲线拟合的进化策略，进化规划方法并以Ｇ ａｍｍａ曲线，指数－对数曲线，指数曲线为例，测试了该类方法的效果，结果表明其性能良好，可望成为各类医用非线性曲线拟合的有效工具。     

免疫细胞离子通道的可塑性

用斑片电压钳位技术(Patch-clamp vecording techniquc)可对免疫系统的细胞中的离子通道进行详细的研究,这些研究已揭示出免疫系统与神经系统的通道十分相似,其中最引人注目的是通道表达及其功能是可调节的。免疫细胞的通道可塑性有几种形式:T淋巴细胞在发育期间及发育成熟后(如成熟细胞与丝裂原相互作用时)所表达的整个K~+通道以细胞成熟的典型方式发生改变;粘附于固体基质可改变巨噬细胞的导电性质:在细胞激活期间,T细胞的Ca~(2+)通道被IP_3开放,中性粒细胞的Ca(~2+)通道被细胞内Ca~(2+)开放。这些研究表明,在分化的早期阶段和随后对环境刺激的反应过程中,免疫系统细胞的“导电现象”发生变化,这可能与细胞的功能有关。     

Markov链模型在蛋白质可溶性预测中的应用

利用Markov链模型对蛋白质可溶性特性进行统计建模，按照蛋白质序列中残基的相对可溶性，将其分为两类（表面／内部）和三类（表面／中间／内部）进行预测。选择不同MCM阶数和分类阈值对数据进行训练和预测，以确保得到最好的分类效果。对两种数据集在不同分类阈值下进行分类预测，并将结果同其他已有方法如神经网络、信息论和支持向量机法等进行比较。该方法对蛋白质可溶性的预测精度和相关系数普遍好于或接近其他预测方法，其中对两类分类问题和三类分类问题的最优分类结果分别达到78．9％和67．7％。同时，该方法具有运算复杂度低、耗时短等优点。     

癫痫与离子通道的分子遗传学研究进展

癫痫的发病机制复杂多样 ,其中遗传因素起着重要作用。随着分子遗传学的发展 ,发现已克隆的癫痫基因有数种与离子通道的突变有关。本文介绍了癫痫与钙离子通道、钾离子通道、钠离子通道的关系 ,以及已克隆的上述离子通道基因的突变与癫痫的关系 ,从分子遗传学的角度初步探讨癫痫的发病机制。     

姜黄素对TRP离子通道抑制作用的研究

目的验证瞬时受体电位（TRP）通道在胶质瘤MGR2细胞中的存在,研究姜黄素对TRP通道的电生理影响,探讨姜黄素抑制肿瘤细胞增殖的可能机制。方法体外培养人脑胶质瘤细胞MGR2;利用膜片钳技术检测胶质瘤细胞MGR2的电生理特性,验证并分离TRP离子通道。使用薄荷醇、无Mg2＋内液、酸以及非特异阻断剂2-氨基乙氧基苯硼酸（2-APB）及钆离子（Gd3＋）对TRP通道的敏感性进行检测。记录不同浓度的姜黄素对TRP通道电流幅度的影响。结果神经胶质瘤细胞MGR2是一种非可兴奋细胞,其细胞上表现出TRP离子通道的电生理特性。该通道对薄荷醇不敏感,对酸的反应不明显。对细胞内液低Mg2＋有（24.2±4.1）%的TRP电流增加（n=12,P〈0.05）,200μmol/L2-APB及10μmol/LGd3＋对TRP电流分别有（46.4±4.5）%及（73.2±3.6）%的增加（n=12,P〈0.05）。姜黄素对TRP通道的抑制作用具有浓度依赖性和可恢复性。结论 TRP通道在胶质瘤细胞MGR2中存在,姜黄素对TRP通道的作用具有浓度依赖性,为姜黄素抑制肿瘤增殖的可能机制提供了实验依据。     

基于离子通道的心肌细胞建模与仿真研究进展

综述国际上基于离子通道心肌细胞建模仿真的研究成果和进展,主要对Hodgkin-Huxley,Beeler-Reuter,Luo-Rudy等代表各个不同时期的心肌细胞模型进行了介绍,并对各模型的贡献及其局限性进行了系统分析,展望了基于离子通道心肌细胞建模与仿真研究领域今后的发展趋势。     

糖尿病心肌离子通道重构的研究进展

糖尿病心血管并发症是患者死亡的主要原因,其中重要的临床表现是与猝死相关的心律失常发生率较高。糖尿病患者心电图常出现与心律失常相关的QT间期延长,且心电图的异常可不伴随其它危险因素而独立存在。实验研究也显示糖尿病动物模型的QT间期延长对应心室肌细胞动作电位时     

发作性共济失调与离子通道病的研究进展

发作性共济失调(episodic ataxia,EA)是一类少见的常染色体显性遗传病。可分为以下几类:①发作性共济失调1型(EA1),发作性共济失调伴肌纤维颤搐(EA／myokymia),是由位于12p13上编码电压门控钾离子通道kv1.1α亚单位的基因KCNA1突变引起的。②发作性共济失调2型(EA2),发作性共济失调伴眼球震颤(EA2／nystagmus),是由于编码P／Q型钙离子通道Cav2.1α,亚单位的基因CAC-NA1A突变造成的,突变位于19p13上。③阵发性舞蹈手足徐动症伴发作性共济失调(paroxysmalchoreoathetosis with episodic ataxia),基因定位于1p上,与钾离子通道有关。     

The on-line direct fitting of low signal-noise ratio single ion channel recordings based on hidden Markov models

INTRODUCTION　　 As fundamental elements of the neural system,ion channels are proteinmolecules spanning in the membrane of excitable cells. They form pores thathave asmall number of discrete conformations. In some of the conformations,the pore isopen and…     

细胞膜离子单通道信号的统计重构算法研究

离子单通道信号是皮安级的随机离子流,用膜片钳技术可以记录下来,但由于信号的微弱性,记录中通道信号往往被背景噪声所淹没,传统上用阈值检测器消除噪声并重构信号,但信噪比低时,阈值检测器失效,本文提出了基于最大后验概率的状态估计和最大似然函数的序列估计两种信号的统计重构技术,在白色背景噪声和有色背景噪声情况下,分别进行仿真实验,证实其重构精度较高,鲁棒性较强,性能远比阈值检测器优越。     

Channelopathies: ion channel defects linked to heritable clinical disorders

Electrical signals are critical for the function of neurones, muscle cells, and cardiac myocytes. Proteins that regulate electrical signalling in these cells, including voltage gated ion channels, are logical sites where abnormality might lead to disease. Genetic and biophysical approaches are being used to show that several disorders result from mutations in voltage gated ion channels. Understanding gained from early studies on the pathogenesis of a group of muscle diseases that are similar in their episodic nature (periodic paralysis) showed that these disorders result from mutations in a gene encoding a voltage gated Na⁺ channel. Their characterisation as channelopathies has served as a paradigm for other episodic disorders. For example, migraine headache and some forms of epilepsy have been shown to result from mutations in voltage gated Ca²⁺ channel genes, while long QT syndrome is known to result from mutations in either K⁺ or Na⁺ channel genes. This article reviews progress made in the complementary fields of molecular genetics and cellular electrophysiology which has led to a better understanding of voltage gated ion channelopathies in humans and mice.


Keywords: ion channel genetics; ion channel physiopathology; channelopathies; hereditary diseases     

自回归模型和隐马尔可夫模型在癫痫脑电识别中的应用

目的研究自回归(autoregressive model,AR)模型和隐马尔可夫模型(hidden Markov model,HMM)在癫痫脑电(electroencephalogram,EEG)识别中的应用,以期减轻医生工作量,减少人工识别主观因素的影响。方法使用基于联合信息准则(combined information criterion,CIC)的最佳阶数AR模型对脑电信号进行特征提取,连续密度隐马尔可夫模型(continuous density hidden Markov model,CD-HMM)作为正常脑电和癫痫脑电的分类工具,对南京军区总医院的临床脑电数据(8组采样频率为512 Hz的16导正常、癫痫脑电信号)进行分析和识别。实验时对每一例样本选取T3、T4、FP1、FP2、C3、C4六个导联的数据。使用训练集中的15段样本进行HMM建模,剩下35段用作测试。结果癫痫脑电的识别率可达90%。结论 AR模型结合HMM建模的方法对正常脑电信号和癫痫脑电的识别率较高,在脑-机接口设备的开发中有一定的应用前景。     

A novel method for analysis of single ion channel signal based on wavelet transform

A single ion channel signal was analysed by the power distribution fraction constructed by a discrete wavelet transform. Average opening time and energy distribution of the signal can be obtained directly by this method. The method can also be used when the signal is corrupted by noise. By contrast, the conventional frequency domain analysis method--power spectral density--is less effective. Power distribution fraction will therefore give more useful information in analysis of experimental ion channel signals, principally by giving values of the mean channel opening time. The method may be applied to distinguish different ion channels more efficiently and to find their reactions to drugs.     

Stochastic behaviour of ion channels in varying conditions

The opening and closing of a single ion channel can be describedas the aggregation into two sets of states, open and shut, ofan underlying Markov process with a finite number of states.In this paper we consider an inhomogeneous process due to changingphysical conditions, in particular a pulse of activity in whichthe transition rates during the pulse differ from those obtainingboth before and after the pulse. Outside the pulse the chaincontains an absorbing shut subset, so that no activity is observedbefore the pulse and, almost surely, at most a finite numberof openings are generated by the pulse. We consider, in particular,the probability distribution of first latency (the time to firstopening) and the distribution of the total activation time.We take into account the phenomenon of time-interval omission,when short open or shut times fail to be observed.     

A model of ion channel kinetics based on deterministic,chaotic motion in a potential with two local minima

Models of the gating of ion channels have usually assumed that the switching between the open and closed states is a random process without a mechanistic basis. We explored the properties of a deterministic model of channel gating based on a chaotic dynamic system. The channel is modeled as a nonlinear oscillator, that has a potential function with two minima, which correspond to the stable open and closed states, and is driven by a periodic driving force. The properties of the model are like some properties of single channel data and unlike other properties. The model is like the data in that: the current switches between two well-defined states, this switching is nonperiodic, and there are subconductance states. These subconductance states are subharmonic resonances, due to the nonlinearities in the equation of the model, rather than stable conformational states due to local minima in the potential energy. The model is not like the data in that the current fluctuates too much within in each state and there are sometimes periodic fluctuations within a state. At the present time, the selection of the most appropriate channel model (Markov, chaotic, or other) is not possible, and in addition to chaotic models, other nonlinear models may be suitable.     

基于MATLAB的隐马尔可夫模型预测蛋白质结构类

目的 准确预测蛋白质结构类,为研究其空间结构及生物功能打下基础.方法 应用隐马尔可夫模型(HMM)预测蛋白质结构类,分别构建3-状态HMM和8-状态HMM.数据来源于Chou和Zhou构建的蛋白质数据集,分别包含有204条蛋白质序列和498条蛋白质序列,通过留一法预测其准确率.结果 所构建的3-状态HMM和8-状态HMM对全α类的预测准确率最高,尤其是3-状态HMM的预测准确率达到95％以上.与Chou数据集相比,Zhou数据集对于全β类和α/β类的预测准确率也有所提高,同时,总体预测率也提高了2％左右;但α+β类的预测准确率有所下降.结论 将整条蛋白质序列作为预测模型的输入信息所构建的HMM模型能有效地预测蛋白质的结构类.     

Dependence of single channel properties of the N-methyl-d-aspartate ion channel on stereoisomer agonists

The cell-attached patch-clamp configuration has been used to determine the single channel properties of the N-methyl-D-aspartate (NMDA) ion channel with activation of the NMDA receptor by stereoisomer agonists. All of the agonists studied, including the L and d forms of N-methyl-aspartate and the L and d forms of homocysteate, activated a 42-pS conductance channel in cultured hippocampal neurons. For all agonists, the mean open times of the channel were diminished with increased patch hyperpolarization and exhibited an exponential dependence on potential over the range -40 mV to -120 mV. The mean open times, for patch potentials close to resting potential, and the mean frequencies of channel openings, at all patch potentials, were significantly different between each member of the stereoisomer pairs. For both L-homocysteate and NMLA, a fourfold increase in the patch pipette concentration caused an approximate quadrupling in the frequency of unitary events, with no significant change in mean open time. The open channel probability was used as a measure of agonist potency, and, at a concentration of 30 M, NMDA and L-homocysteate were significantly more potent (P open in excess of 1.5%) than the corresponding stereoisomer compounds NMLA and D-homocysteate (P open near 0.3%). The relative potencies of the stereoisomer pairs were in reasonable agreement with the potency ratios measured in binding studies.