How X-Rays Are Shedding Light on Our Understanding of Heart Function

Sunday, February 17, 2013
Room 207 (Hynes Convention Center)
Filip van Petegem , University of British Columbia, Vancouver, BC, Canada
The contraction of muscle tissue (cardiac and skeletal muscle) is a tightly regulated event.  The major signal that triggers the event is formed by calcium ions (Ca2+).  Whereas the cytoplasmic levels are extremely low, Ca2+ can be stored inside organelles like the sarcoplasmic reticulum (SR). The Ca2+ ions can be released from the SR through specialized ion channels known as ‘Ryanodine Receptors’ (RyRs). RyRs form huge macromolecular assemblies that are under intense regulation. They are also the target for several disease mutations that can cause severe cardiac and skeletal muscle disorders. CPVT, for example, is a condition that is triggered by physical or emotional stress and results in cardiac arrhythmias and sudden cardiac death. Malignant hyperthermia is the result of a massive rise in body temperature upon administration of volatile anesthetics.

Here I describe our structural insights into these disease mechanisms.  By combining low-resolution and high-resolution data, we can locate the positions of ~100 disease mutations in the 3D structure of the Ryanodine Receptor. In addition, we can look at the allosteric movements the receptor undergoes as the channel is opening and closing.  We found that disease mutations target the interfaces between various domains. By weakening such contacts, they facilitate the movements to open the channel, resulting in premature or prolonged release of Ca2+ into the cytoplasm. The result can be deadly:  the Ca2+ leak can trigger additional electrical signals that underlie arrhythmias, or create a short-circuit, whereby the muscle cells use up all of their energy supplies  to continuously pump Ca2+ back into the SR.