Towards a Structural Basis of Complex Disorders of Heart, Muscle and Brain

Ryanodine receptors (RyR) are intracellular calcium-release channels found in almost all cell types. Andrew Marks and his team recently solved the high-resolution structure of the skeletal muscle form, RyR1. The structure provides insight regarding how dysfunctional RyR channels contribute to common diseases, including heart failure, muscular dystrophy and Alzheimer’s disease.

In this lecture, Dr. Marks will present new data on the high-resolution structure of the mammalian RyR1/intracellular calcium-release channel obtained using cryogenic electron-microscopy. Chronic stress mediated by oxidation and phosphorylation of the channel render it ‘leaky.’ This results in a pathological intracellular calcium leak from the sarcoplasmic/endoplasmic reticuli. This intracellular calcium leak causes distinct pathologies in different tissues. In cardiac muscle, RyR leak contributes to heart failure and cardiac arrhythmias. In skeletal muscle, RyR leak contributes to muscle weakness in muscular dystrophies and cancer metastatic to bone. In the brain, leaky RyR channels contribute to cognitive dysfunction in post-traumatic stress disorder and Alzheimer’s disease.