Molecular and functional diversity of cloned cardiac potassium channels.
Molecular and functional diversity of cloned cardiac potassium channels.
复制标题
克隆心脏钾通道的分子和功能多样性。
DOI：
10.1007/bf00877624
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发表时间：
1993
影响因子：
3.4
通讯作者：
Tamkun,MM
中科院分区：
文献类型：
--
作者：
Bennett,PB;Po,S;Snyders,DJ;Tamkun,MM
动作电位时程是心脏组织不应性的重要决定因素，因此也是传播电脉冲能力的重要决定因素。动作电位持续时间部分由K+电流的激活控制。阻断K+通道并由此延长动作电位时程已成为越来越有吸引力的抗心律失常干预模式。由于心肌细胞中存在多种类型的K+通道以及难以分离单个电流，因此对单个心脏K+通道的详细研究受到阻碍。我们已经通过采用组合分子克隆技术、异源通道表达系统和表达通道的生物物理分析来解决这个问题。我们重点研究了从大鼠和人类心血管系统克隆的六种不同的通道。每个通道具有独特的功能和药理学特征，并且作为一个组，它们包括一系列哺乳动物K+通道亚型，这些亚型可以解释哺乳动物心脏中通道的一些多样性。每个通道似乎由不同的基因编码，很少或没有证据表明RNA转录物的选择性剪接可以解释一级氨基酸序列的差异。除了这些通道亚型表达为同源四聚体组装体时的独特动力学性质外，还观察到异源四聚体K+通道的形成。从不同的基因产物中形成异源四聚体通道，以创建具有独特动力学和药理学特性的新通道，这可能进一步解释了心脏K+通道的多样性。
Action potential duration is an important determinant of refractoriness in cardiac tissue and thus of the ability to propagate electrical impulses. Action potential duration is controlled in part by activation of K+currents. Block of K+channels and the resultant prolongation of action potential duration has become an increasingly attractive mode of anti-arrhythmic intervention. Detailed investigation of individual cardiac K+channels has been hampered by the presence of multiple types of K+channels in cardiac cells and the difficulty of isolating individual currents. We have approached this problem by employing a combination molecular cloning technology, heterologous channel expression systems, and biophysical analysis of expressed channels. We have focused on six different channels cloned from the rat and human cardiovascular systems. Each channel has unique functional and pharmacological characteristics, and as a group they comprise a series of mammalian K+channel isoforms that can account for some of the diversity of channels in the mammalian heart. Each channel appears to be encoded by a different gene with little or no evidence for alternate splicing of RNA transcripts to account for the differences in primary amino acid sequence. In addition to the unique kinetic properties of these channel isoforms when expressed as homotetrameric assemblies, the formation of heterotetrameric K+channels is also observed. The formation of heterotetrameric channels from the different gene products to create new channels with unique kinetic and pharmacological properties might further account for cardiac K+channel diversity.