Grant: Operating Grant

What do calcium ions and deadly fever have in common? Known mostly for their importance in maintaining bone structure, calcium ions have many other important functions in every cell of our bodies. One of their tasks includes the contraction of muscle tissue. At the cellular and molecular level, the contraction of muscle is a very complex event. One of the key steps involves moving calcium ions from one compartment in the muscle cell (known as the sarcoplasmic reticulum) to another (known as the cytoplasm). When there is a sufficient amount of calcium in the cytoplasm, the muscle cell contracts. However, the exact amount of calcium is absolutely crucial: too little or too much calcium can cause severe diseases. This proposal deals with one of these diseases. Malignant Hyperthermia is a disorder that mostly affects patients during surgery. Upon the administration of particular anesthetics, these patients experience a massive rise in body temperature, which is fatal in more than 80% of the cases. The cause for this disease is particular mutations in a protein known as "RYR1". This protein forms a doorway through which calcium ions can move into the cytoplasm. This door can open and close, and when it opens too soon, a deadly fever may be the consequence. The combination of anesthetics and a mutation in RYR1 can cause exactly this. This is why patients can appear perfectly normal, and problems only arise during surgery. In this proposal, we wish to find out the exact mechanisms by which the disease mutations affect the RYR1 protein. We study the exact three-dimensional structure of the protein using advanced techniques, and look at the effect of genetic disease mutations.