KCNE1 as a molecular shield of KV7.1

KCNE1作为KV7.1的分子盾

基本信息

项目摘要

Project Summary (Abstract): The proposed work seeks to identify the molecular basis for a novel interaction between two proteins that are typically found in electrically active cells such as neurons and cardiac muscles cells. One of the proteins is known as a voltage-dependent, potassium-selective KV7.1 channel. This protein, hereafter KV7.1, is a major player for the termination of fast electrical signals. For instance, KV7.1 is critical for terminating each cycle of the rhythmic electrical signaling in the heart. In fact, a faulty, low-performing KV7.1 leads to arrhythmias that, in some cases, can unchain fibrillations that result in death. In the auditory system, such alterations lead to hearing disorders and deafness. The second protein is known as NaVβ1. This is an auxiliary subunit that regulates the activity of sodium-selective, voltage-dependent (NaV) channels which are responsible for initiating fast electrical signals. NaVβ1 is an important positive regulator of NaV channels. In a few words, NaV starts an electrical signal event, and KV7.1 contributes to its termination. What is novel here is that NaVβ1 not only boosts the activity of NaV channels, but also decreases the activity of KV7.1 as we have recently found. Furthermore, we found that a fourth protein, KCNE1 can protect KV7.1 from the inhibitory action of NaVβ1. Like with the pair NaVβ1-NaV channel, KCNE1 can increase the activity and expression of KV7.1 channels. In cells that express these four proteins, we will find NaV channels associated with NaVβ1 and KV7.1 channels associated with KCNE1. In the absence of KCNE1, our recent data suggest that, while boosting that of NaV channels, NaVβ1 will decrease KV7.1 activity. In this case, the ON-OFF balance of events generating fast electrical signals will be altered, leading to abnormal electrical events. Our novel finding constitutes a shift in our understanding of how mutations in KCNE1 can affect cellular electrical signaling. If KCNE1 is mutated, KV7.1 activity could be lower due to such mutation, but also could be further decreased by the action of NaVβ1. Some mutations in KCNE1 have been shown to cause little alteration in the activity of the KCNE1/KV7.1 complex when compared with the non-mutated pair. Yet such mutations are linked to diseases. This apparent disconnect may emerge from not considering the action of NaVβ1, which could have been gone undetected. This proposal aims at addressing this issue by expanding our understanding of the effect of mutations in KCNE1 in term of its ability to shield KV7.1 from the action of NaVβ1. The outcomes of this work will provide a novel paradigm in which KCNE1 is not only a positive modulator of KV7.1 channels, but also a molecular shield protecting these channels from the action of other regulatory subunits.
项目摘要(摘要): 这项拟议的工作试图确定一种新的相互作用的分子基础 通常存在于神经元和心肌等电活动细胞中的蛋白质 细胞。其中一种蛋白被称为电压依赖的钾选择性KV7.1通道。 这种蛋白质,以下简称KV7.1,是终止快速电信号的主要参与者。为 例如,KV7.1对于终止每个周期的有节奏的电信号是至关重要的 心。事实上,有缺陷、性能低下的KV7.1会导致心律失常,在某些情况下,可能会 使导致死亡的纤颤解链。在听觉系统中,这样的变化会导致听力。 精神紊乱和耳聋。第二个蛋白质被称为NAVβ1。这是一个辅助亚基, 调节钠选择性电压依赖(NAV)通道的活性 负责发出快速电信号。NAVβ1是NAV的重要正性调节因子 频道。简而言之,NAV启动了一个电信号事件,KV7.1为其 终止。这里的新奇之处在于,NAVβ1不仅增强了NAV通道的活性,而且 也会降低我们最近发现的KV7.1的活性。此外,我们发现一个 第四个蛋白,KCNE1.可以保护KV7.1不受NAVβ1的抑制作用。 NAVKV1-NAV通道,β可增加KV7.1通道的活性和表达。在单元格中 表达这四种蛋白,我们将发现与NAVβ1和KV7.1相关的NAV通道 与KCNE1关联的频道。在没有KCNE1的情况下,我们最近的数据表明,虽然 NAVβ1可增强NAV通道的活性,降低KV7.1的活性。在本例中,打开-关闭 产生快速电信号的事件平衡会改变,导致异常电信号 事件。我们的新发现改变了我们对KCNE1基因突变的理解 会影响细胞的电信号。如果KCNE1发生突变,KV7.1活性可能会降低,原因是 这样的突变,也可以通过NAVβ1的作用进一步减少。 KCNE1已被证明对KCNE1/KV7.1复合体的活性几乎没有影响 与未突变的那对相比。然而,这种突变与疾病有关。这 如果不考虑NAVβ1的作用,可能会出现明显的脱节 一直没有被发现。这项提案旨在通过扩大我们的 了解KCNE1基因突变对KV7.1的保护作用 这项工作的结果将提供一种新的范式,其中β不是 不仅是KV7.1通道的正向调制器,而且还是保护这些通道的分子屏蔽物 渠道不受其他调节亚单位的影响。

项目成果

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