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

与现代计算机类似，我们大脑和身体中的神经功能需要微小的组件来调节电荷运动和电压变化，以准确地在正确的时间和地点。然而，与计算机不同的是，由于其有机性质，我们体内的电活动也会对化学和物理环境做出反应。控制神经中电活动的微小成分称为离子通道，它们控制带电粒子以钾、钠、氯和钙离子的形式穿过细胞膜的运动。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，既具有科学意义，也有助于开发可以微调其活性的药理学工具。在这项研究计划中感兴趣的蛋白质是钾通道，它主要对细胞内钠离子的存在做出反应，其次是膜电压。这些钾离子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40年里，实验室技术已经存在，能够从单个细胞甚至单个离子通道分子记录通过离子通道穿过细胞膜的电荷流。这使得研究人员能够从功能的角度来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。在显微镜技术中有一些令人兴奋的发展，可以获得蛋白质结构的静态图像。同样，计算工具也已经开发出来，使我们能够显示这些蛋白质分子在某些条件下如何改变形状。我们的研究提案旨在将这些最先进的技术结合在一起，以了解这些钾通道如何工作的分子基础，以及它们如何对钠离子的存在和膜电压的变化做出反应。在进行这项研究时，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，调整蛋白质的行为，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，这些化学物质可用于进一步的实验，以更好地了解这些蛋白质在整个身体中所起的作用。这些也可能是开发药理学和治疗方法的起点，用于整个生命周期的各种人类状况。

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.