KCNQ1突变基因导致LQTS的新机制研究及乙醇对KCNQ1通道的影响

发布时间：2018-01-01 06:30

本文关键词：KCNQ1突变基因导致LQTS的新机制研究及乙醇对KCNQ1通道的影响　出处：《华中科技大学》2005年硕士论文　论文类型：学位论文

【摘要】：离子通道是细胞膜上的蛋白质孔道,离子的跨膜流动是细胞传递信息的基础。钾通道是一类普遍存在的膜蛋白,在很多的生理过程中扮演着极为重要的角色。KCNQ基因编码的是一个电压依赖的钾离子通道家族。KCNQ 基因发生突变,就会导致很多“离子通道病”的发生,主要是先天性长QT 综合征(long QT syndrome,LQTS)。简要介绍了KCNQ1 基因和其编码的通道蛋白的结构、生理学功能及电生理特点。归纳了围绕KCNQ1 基因的热点研究方向和成果,对KCNQ1 基因突变与疾病的关系及相关的病理药理学研究做了较为详细的介绍。利用非洲爪蟾卵母细胞表达系统和双电极电压钳技术,研究了新发现的两个与LQTS 相关的错义突变(L191P 和F275S)的作用机制。L191P 和F275S 能将野生型的KCNQ1 电流减小70%。电导-电压曲线向正电压方向偏移约20～40 mV。激活、去激活速率都被减慢。F275S/minK表达的电流还表现出失活。野生型与突变型KCNQ1以1:1 比例共表达时,突变型KCNQ1 表现出负显性作用。此外,L191P 和F275S 都减小了单通道电导。负显性作用是通过KCNQ1 亚基与其调节亚基(KCNE1 蛋白)的结合产生的,而不是因为突变通道的失活。这可以说明中国LQTS 病人心律不齐的分子机制。利用同样的实验技术,还研究了乙醇对KCNQ1 和KCNE1 共同编码的延迟整流型钾电流(IKs)各种特性的影响。20～500 mmol/L 的乙醇对IKs的抑制呈浓度依赖性,半数抑制浓度为137.3±6.39 mmol/L。抑制作用发生迅速,在换液2 分钟后抑制水平就能保持稳定。乙醇还使钾通道的激活曲线向右偏移,说明通道的门控特性被改变。乙醇可能是直接结合于钾离子通道蛋白的疏水区而起抑制作用的。研究结果为阐明乙醇对心肌细胞的影响机制提供了有关钾离子通道方面的资料。
[Abstract]:Ion channel is a protein channel on cell membrane, and ion transmembrane flow is the basis of cell transmission information. Potassium channel is a kind of ubiquitous membrane protein. KCNQ gene plays a very important role in many physiological processes. KCNQ gene encodes a voltage-dependent potassium channel family. This may lead to many "ion channel diseases", mainly long QT syndromes long QT syndromes and LQTSN. In this paper, the structure, physiological function and electrophysiological characteristics of KCNQ1 gene and its encoded channel protein are briefly introduced, and the hot research directions and achievements about KCNQ1 gene are summarized. The relationship between KCNQ1 gene mutation and disease and the related pathological pharmacology were introduced in detail. Xenopus laevis oocyte expression system and double electrode voltage clamp technique were used. Two new missense mutations associated with LQTS, L191P and F275S, were studied. L191P and F275S can reduce the wild-type KCNQ1 current by 70%, and the conductance voltage curve shifts to the positive voltage direction about 2040 MV. The rate of deactivation was reduced. The current expressed at .F275S / min K also showed inactivation. When wild-type and mutant KCNQ1 were coexpressed at 1: 1. Mutant KCNQ1 showed negative dominant effect. Both L191P and F275S reduced the single channel conductance. The negative dominant effect was produced by the binding of KCNQ1 subunit to its regulated subunit KCNE1 protein. This suggests the molecular mechanism of arrhythmia in LQTS patients in China. Using the same experimental techniques. The delayed rectifier potassium current (IKS) coencoded by ethanol on KCNQ1 and KCNE1 was also studied. The inhibition of IKs by ethanol at 20 ~ 500 mmol/L was concentration-dependent. The half inhibitory concentration was 137.3 卤6.39 mmol / L. The inhibition occurred rapidly, and the inhibition level remained stable 2 minutes after the change of solution. Ethanol also made the activation curve of potassium channel shift to the right. The results suggest that the gated characteristics of the channel have been changed. Ethanol may be directly bound to the hydrophobic region of potassium channel protein and inhibit the effect of ethanol on myocardial cells. The results of the study provide a relevant potassium ion flux for elucidating the effect of ethanol on cardiomyocytes. Information on Tao.
【学位授予单位】：华中科技大学
【学位级别】：硕士
【学位授予年份】：2005
【分类号】：R363

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