Understanding the structural basis of sodium-triggered activation of neuronal potassium channels

了解钠触发神经元钾通道激活的结构基础

• 批准号: BB/X007251/1
• 负责人: Jonathan Lippiat
• 金额: $ 67.14万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX007251%2F1
• 关键词: Understanding; structural; basis; sodium; triggered

Similar to modern computers, the function of nerves throughout our brain and body requires tiny components to regulate charge movement and changes in voltage at exactly the right time and place. Unlike computers, however, the electrical activity in our body also responds to the chemical and physical environment due to its organic nature. The tiny components that control electrical activity in nerves are called ion channels and they control the movement of charged particles in the form of potassium, sodium, chloride, and calcium ions across the cell membrane. Understanding how they work and how they contribute to the normal functioning of the human body is of both scientific importance and also for the development of pharmacological tools that can fine-tune their activity. The protein of interest in this research proposal are potassium channels that respond primarily to the presence of sodium ions inside cells and secondarily the membrane voltage. These potassium channels are required for our brains and bodies to develop normally, and to understand and feel the world around us.Over the last forty years, laboratory techniques have existed that enable the charge flow across cell membranes through ion channels to be recorded from individual cells and even individual ion channel molecules. This has enabled researcher to describe how ion channels behave from the functional point of view. What researchers lack, however, is a description of what the proteins look like and how their structures change from one moment to the next in response to chemical and physical triggers. There have been some exciting developments in microscopy that enable static images of protein structures to be obtained. Similarly, computational tools have also been developed to allow us to show how these protein molecules change shape under certain conditions. Our research proposal aims to bring these state-of-the-art techniques together to understand the molecular basis of how these potassium channels work and how they respond to the presence of sodium ions and changes in membrane voltage.In carrying out this research, we will identify parts of the protein structure that could be targeted by chemicals to fine-tune the protein behaviour and will use computational tools to predict which chemicals may work. In doing so we will identify chemicals that either increase or decrease potassium channel function that could be used in further experiments to better understand the roles played by these proteins throughout the body. These may also be starting points for developing the pharmacology and therapeutics for diverse human conditions across the lifespan.

与现代计算机类似，贯穿我们大脑和身体的神经功能需要微小的组件来精确地在正确的时间和地点调节电荷运动和电压变化。然而，与电脑不同的是，由于人体的有机性质，我们体内的电活动也会对化学和物理环境做出反应。控制神经电活动的微小成分被称为离子通道，它们控制以钾、钠、氯和钙离子形式存在的带电粒子穿过细胞膜的运动。了解它们是如何工作的，以及它们如何促进人体的正常功能，不仅具有科学意义，而且对于开发能够微调它们活动的药理学工具也具有重要意义。本研究计划中感兴趣的蛋白质是钾通道，钾通道主要对细胞内钠离子的存在作出反应，其次是膜电压。这些钾通道是我们大脑和身体正常发育所必需的，也是我们理解和感受周围世界所必需的。在过去的四十年里，实验室技术已经能够记录单个细胞甚至单个离子通道分子在细胞膜上通过离子通道流过的电荷。这使研究人员能够从功能的角度描述离子通道的行为。然而，研究人员缺乏的是对蛋白质外观的描述，以及它们的结构如何在化学和物理触发下从一个时刻到下一个时刻发生变化的描述。显微镜学有了一些令人兴奋的进展，可以获得蛋白质结构的静态图像。同样，计算工具也被开发出来，使我们能够展示这些蛋白质分子在特定条件下如何改变形状。我们的研究计划旨在将这些最先进的技术结合在一起，以了解这些钾离子通道如何工作的分子基础，以及它们如何响应钠离子的存在和膜电压的变化。在进行这项研究的过程中，我们将确定蛋白质结构的某些部分，这些部分可以被化学物质靶向，以微调蛋白质的行为，并将使用计算工具来预测哪些化学物质可能起作用。在此过程中，我们将确定增加或减少钾通道功能的化学物质，这些化学物质可以用于进一步的实验，以更好地了解这些蛋白质在全身所起的作用。这些也可能是开发针对不同人类生命条件的药理学和治疗方法的起点。