Developing novel therapeutic targets to treat arrhythmia-causing ryanodine receptor variants in the heart
Our hearts play a crucial role to distribute blood throughout our bodies. When it beats irregularly, also called an arrhythmia, it can lead to major fatigue, loss of consciousness, or even death in some of the most serious cases. Arrhythmias can either be acquired throughout our lives or have genetic forms. The latter are more rare, but are usually more severe and affect very young people. In this project, we study a genetic form of arrhythmia that is due to mutations in a gene encoding "RyR2". RyR2 is very large protein that is present in all of our heart muscle cells, and its function is critical for the heartbeat. In particular, it allows calcium ions to move inside the heart muscle cells to maintain regular heartbeat patterns. The mutations, found in various families worldwide, affect the RyR2 protein directly, such that the calcium ions move too easily. We aim to understand how this happens, by solving the 3D structures of the ‘normal’ RyR2, and of RyR2 with a disease mutation. This comparison will allow us to look at the precise effect of the mutation on the structure of RyR2 and on how it functions. The 3D structures will also help with generating novel drugs that can help treat arrhythmia.