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

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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.