Grant: CIHR Fellowship

The beating of our hearts is a complex biochemical event. It relies on electrical signals, which can sometimes be disturbed, resulting in potentially fatal cardiac arrhythmias. One of the key component involved in the contraction of heart muscle is a small ion known as calcium. Just prior to the contraction, calcium rushes into heart cells and triggers the contraction. Having the right amount of calcium at the right time is thus key for our regular heart rhythms, and too much or too little entry of calcium can be potentially fatal. The different compartments within the heart muscle cell are separated by membranes, which form barriers for many molecules. The calcium ions required for contraction of the heart muscle cells must pass through special gates. The sites where it all happens are formed by highly specialized protein channels that can open and close, thus determining the amount and timing of calcium release from one compartment to another. The most important of these so-called 'calcium channels' is a large protein with the name 'Ryanodine Receptor'. The gene that encodes this protein is among the largest genes known with literally hundreds of mutations documented to cause arrhythmias. In collaboration with several cardiologists who specialize in arrhythmias, we aim to determine how exactly the various mutations in this gene lead to the arrhythmias as a step to developing therapeutics. In order to do this, it is necessary to know the overall 3D structure of the calcium channel. To do this, make use of a highly specialized technique termed "X-ray crystallography". By shooting X-rays at crystals of the channel and analyze the way these rays scatter off the atoms in the crystal, we can figure out via complex calculations, what the 3D structure looks like. By comparing structures of the calcium channels of normal and diseased individuals, we can directly observe the mechanisms of the disease-causing mutations and discover potential therapeutic strategies.