Project 460689

Many cells in our bodies rely on electrical signals. This includes neurons, but also heart muscle and skeletal muscle cells. These cells are surrounded by a membrane, which forms a physical barrier for many molecules. Embedded within these membrane are specialized proteins that are responsible for the electrical signals. Also known as "ion channels", these proteins form gateways for various ions to move into our out of the cell. As these ions carry electrical charge, this movement is what shapes the electrical signals. Because these electrical signals affect the ability of our brains to compute information, and the ability of our hearts to beat in a rhythmic fashion, it is paramount that they are regulated properly. Any small deviation in their regulation can cause devastating and life-threatening conditions, such as heart rhythm disorders. In this proposal, we aim to understand how these ion channels are regulated by calcium ions. Curiously, these calcium ions first enter the cells through the ion channels, and then provide a signal to these channels to 'shut down'. How exactly this process happens is currently not known. We will tackle this problem by using very advanced imaging methods. As proteins like ion channels are too small to be observed via regular microscopes, we instead rely on electron microscopy. We collect hundreds of thousands of images of these channels, which are then superposed onto one another to enhance the contrast. By collecting images from different view angles, we can then determine the 3D structure of the protein. This methodology has advanced considerably in the last few years, and can give near-atomic level resolution of the protein. In doing so, we will analyze the effect of calcium ions on the structure. We will also investigate how genetic mutations, linked to heart rhythm disorders, change the structure of these ion channels. This will give much-needed fundamental insights into the origins of cardiac arrhyhtmia.