KCNE1 as a molecular shield of KV7.1

KCNE1作为KV7.1的分子盾

基本信息

批准号：
10650087
负责人：
Carlos Alberto Villalba-Galea
金额：
$ 19.55万
依托单位：
UNIVERSITY OF THE PACIFIC-STOCKTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650087
关键词：
Address Affect Amino Acids Architecture Arrhythmia Auditory system Brain Cardiac Myocytes Cell membrane Cells Cessation of life Characteristics Clinical Complex Data Dependence Disease Encephalopathies Engineering Equilibrium Ethers Event Exposure to Family Family member Genes Glycine Hearing problem Heart Human Kinetics Lead Leucine Link Literature Membrane Membrane Potentials Modeling Modification Molecular Muscle Cells Mutate Mutation Neurons Nonsense Mutation Oocytes Organ Outcome Periodicity Potassium Predisposition Process Protein Isoforms Proteins RNA Splicing Recovery Signal Transduction Sodium Testing Transmembrane Domain Ventricular Work Xenopus oocyte amino group cell type deafness disease-causing mutation extracellular novel prevent virtual voltage

Address Affect Amino Acids Architecture Arrhythmia Auditory system Brain Cardiac Myocytes Cell membrane Cells Cessation of life Characteristics Clinical Complex Data Dependence Disease Encephalopathies Engineering Equilibrium Ethers Event Exposure to Family Family member Genes Glycine Hearing problem Heart Human Kinetics Lead Leucine Link Literature Membrane Membrane Potentials Modeling Modification Molecular Muscle Cells Mutate Mutation Neurons Nonsense Mutation Oocytes Organ Outcome Periodicity Potassium Predisposition Process Protein Isoforms Proteins RNA Splicing Recovery Signal Transduction Sodium Testing Transmembrane Domain Ventricular Work Xenopus oocyte amino group cell type deafness disease-causing mutation extracellular novel prevent virtual voltage

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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）：拟议的工作旨在确定两者之间新型相互作用的分子基础通常在电动细胞（例如神经元和心肌）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。该蛋白质（此后KV7.1）是终止快速电信号的主要参与者。为了实例，KV7.1对于终止节奏电信号的每个循环至关重要心。实际上，不良，表现低的KV7.1导致心律不齐，在某些情况下可以脱链纤颤，导致死亡。在听觉系统中，这种更改导致听力疾病和耳聋。第二蛋白称为NAVβ1。这是一个辅助亚基调节钠选择性，电压依赖性（NAV）通道的活性负责启动快速电信号。 NAVβ1是NAV的重要积极调节剂频道。用几句话，导航启动电信事件，而KV7.1有助于其终止。这里的新颖是，NAVβ1不仅可以增强NAV通道的活性，还可以正如我们最近发现的那样，还降低了KV7.1的活性。此外，我们发现第四蛋白KCNE1可以保护KV7.1免受NAVβ1的抑制作用。就像这对 NAVβ1-NAV通道，KCNE1可以增加KV7.1通道的活性和表达。在细胞中表达这四种蛋白质，我们将发现与NAVβ1和KV7.1相关的NAV通道与KCNE1相关的通道。在没有KCNE1的情况下，我们的最新数据表明，虽然增加NAV通道的NAVβ1将降低KV7.1活性。在这种情况下，开关生成快速电信号的事件的平衡将被改变，导致电动异常事件。我们的小说发现构成了我们对KCNE1突变的理解的转变会影响细胞电信号传导。如果KCNE1突变，则KV7.1活性可能会降低这种突变，但也可以通过NAVβ1的作用进一步降低。一些突变 KCNE1已被证明会导致KCNE1/KV7.1复合物的活性发生变化很小与非突出对相比。然而，这种突变与疾病有关。这明显的断开可能不考虑NAVβ1的作用，这可能具有没有发现。该建议旨在通过扩展我们的理解KCNE1突变在其能力屏蔽KV7.1方面的影响 NAVβ1的作用。这项工作的结果将提供一个新颖的范式，其中KCNE1不是只有KV7.1通道的正调节器，但也是保护这些的分子屏蔽层来自其他监管亚基的作用的渠道。