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(Abstract): 拟议的工作旨在确定两个之间的新型相互作用的分子基础。 通常在电活性细胞如神经元和心肌中发现的蛋白质 细胞其中一种蛋白质被称为电压依赖性钾选择性KV7.1通道。 这种蛋白质,下文称为KV7.1,是终止快速电信号的主要参与者。为 例如,KV7.1对于终止心脏中节律性电信号的每个周期至关重要。 心事实上,一个有缺陷的,低性能的KV7.1会导致心律失常,在某些情况下, 解开导致死亡的纤维化在听觉系统中,这种改变导致听觉 疾病和耳聋。第二种蛋白质称为NaVβ1。这是一个辅助亚单位, 调节钠选择性电压依赖性(NaV)通道的活性, 负责启动快速电信号。NaVβ1是NaV的重要正调节因子 渠道简而言之,NaV启动电信号事件,而KV7.1有助于其 终止这里的新颖之处在于,NaVβ1不仅增强了NaV通道的活性, 正如我们最近发现的,也降低了KV7.1的活性。此外,我们发现, 第四种蛋白KCNE 1可以保护KV7.1免受NaVβ1的抑制。就像那对 NaVβ1-NaV通道,KCNE 1可增加KV7.1通道的活性和表达。细胞中 在表达这四种蛋白的细胞中,我们将发现与NaVβ1和KV7.1相关的NaV通道。 与KCNE 1相关的通道。在没有KCNE 1的情况下,我们最近的数据表明, NaVβ1可增强NaV通道的活性,降低KV7.1的活性。在这种情况下, 产生快速电信号的事件的平衡将被改变,导致异常的电 事件我们的新发现构成了我们对KCNE 1基因突变的理解的转变。 会影响细胞电信号如果KCNE 1发生突变,KV7.1的活性可能会降低, 这种突变,而且还可以通过NaVβ1的作用进一步减少。中的一些突变 KCNE 1对KCNE 1/KV7.1复合物的活性几乎没有影响 与未突变的一对相比。然而,这种突变与疾病有关。这 不考虑NaVβ1的作用可能会出现明显的脱节, 没有被发现这项建议旨在通过扩大我们的 了解KCNE 1突变的影响,就其保护KV7.1免受 NaVβ1的作用。这项工作的结果将提供一个新的范例,其中KCNE 1不是 不仅是KV7.1通道的正调制器,而且是保护这些通道的分子屏障。 其他调节亚单位的作用。

项目成果

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Carlos Alberto Villalba-Galea的其他文献

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