Voltage-gated sodium channel modulation by Beta1 and Beta4

Beta1 和 Beta4 的电压门控钠通道调制

• 批准号: 9149072
• 负责人: Frank Gert Werner Bosmans
• 金额: $ 35.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9149072
• 关键词: Affect; Amino Acids; Animals; Architecture; Asparagine; Behavior; Biodiversity; Biological Assay; Cardiac; Complex; Data; Disease; Docking; Epilepsy; Extracellular Domain; Fluorescence; Glutamine; Glycoproteins; Goals; Human; Human body; Label; Link; Measures; Membrane Lipids; Membrane Potentials; Modeling; Molecular; Movement; Mutagenesis; Mutation; Outcome; Pattern; Pharmaceutical Preparations; Pharmacology; Predisposition; Property; Protein Isoforms; Resolution; SCN2A protein; Signal Transduction; Sodium; Sodium Channel; Structure; Syndrome; Toxin; Transmembrane Domain; Transplantation; Variant; base; glycosylation; mutant; public health relevance; research study; response; risk variant; sensor; voltage

 DESCRIPTION (provided by applicant) Voltage-activated sodium (Nav) channels form the cornerstones of fast electrical signaling in the human body. On a molecular level, Nav channels consist of four similar domains that each contains a voltage sensor which largely resides within the lipid membrane. These sensors can interact with β1 and β4, two associated glycoproteins that regulate the gating properties of the channel and modulate channel expression levels. Although a link between Nav channel mutations and particular diseases has been established, little is known about the regulatory influence of β1 and β4 on Nav channels and how mutations within these two molecules relate to epilepsy (β1) and cardiac (β4) syndromes. To begin to understand this causal relationship, we need to establish an interaction model that reflects the mechanism by which β1 and β4 regulate the functional properties of the channel. We propose that these β-subunits tune the response of Nav channels to membrane potential changes by influencing voltage-sensing domains. To help examine this notion, we will assess the impact of an epilepsy-related β- subunit mutation on its ability to alter correct signaling complex assembly or modify channel gating. To achieve our goals, we will use Nav1.2 as a model channel since this particular isoform can interact with β1 and β4 and is a risk gene for epilepsy. Although β-subunit crystal structures provide atomic resolution information, a relative orientation in respect to the Nav channel is required to understand their interaction. Identification of anchoring residues in both partners will help orient functional regions within the extracellular and transmembrane domains, thereby providing the experimental basis for docking β1 and β4 onto the Nav channel. The resulting model will offer a starting point to explain mutational effects, which is necessary to accurately interpret and correct pathogenic behavior.

 描述（由适用提供）电压激活的钠（NAV）通道形成了人体快速电信号的基石。在分子水平上，NAV通道由四个相似的域组成，每个域都包含一个电压传感器，该电压传感器主要位于脂质膜内。这些传感器可以与β1和β4相互作用，这两种相关的糖蛋白可以调节通道的门控特性并调节通道表达，尽管已经建立了NAV通道突变与特定疾病之间的联系，但对于β1和β4在NAV通道上对β1和β4在这两个分子中的调节影响却几乎没有任何了解，以及在这两个分子中与ePilesepsecsepsecs和cyndrecss cylecsy（cylepsy）（β4）（β4）相关（β4）。为了开始理解这种灾难性关系，我们需要建立一个相互作用模型，该模型反映了β1和β4调节通道的功能特性的机制。我们建议这些β-套件通过影响电压感应域对NAV通道对膜电位变化的响应进行调整。为了帮助检查这个概念，我们将评估与癫痫相关的β-亚基突变对改变正确信号传导复合物组装的能力的影响 或修改通道门控。为了实现我们的目标，我们将使用NAV1.2作为模型通道，因为该特定的同工型可以与β1和β4相互作用，并且是癫痫的风险基因。尽管β亚基晶体结构提供了原子分辨率信息，但相对方向 需要对NAV频道了解其互动。鉴定两个伴侣中的锚定结果将有助于在细胞外和跨膜结构域内定位功能区域，从而为NAV通道提供对接β1和β4的实验基础。最终的模型将提供解释突变效应的起点，这是准确解释和纠正致病行为所必需的。