Grant: Doctoral: Vanier Canada Graduate Scholarships

People with long QT interval syndrome (LQTS), either congenital or drug-induced, can suffer serious arrhythmias and even sudden death. This research seeks to understand the underlying properties, and therapeutic drug modification of the proteins responsible for LQTS. The IKs current, generated by the pairing of a potassium channel protein called KCNQ1, with accessory subunit proteins, KCNE1 and calmodulin (CaM), together, play a vital role in maintaining normal heart rhythm. As such, drugs which enhance IKs activity have been proposed as a therapeutic strategy to treat LQTS. Mefenamic acid has been identified as one such IKs activator but, how this drug works on a molecular level - example, the drug's binding site(s) - are unknown. Presently, mutations in KCNQ1, KCNE1 and CaM have all been functionally linked to LQTS but whether mefenamic acid can rescue any of these LQTS-causing mutations in KCNQ1, KCNE1 and CaM has not been tested. In addition to examining these questions by electrical analysis using whole-cell patch-clamp and single channel recordings, the second part of our proposed project involves determining, for the first time, the channel's protein structure at a near atomic level using cryo-electron microscopy. By examining how mefenamic acid functions on a molecular level using electrical analysis will allow us to better understand how these channels activate. We can then use this information to help develop more specific and effective treatments for LQTS. In addition, once we uncover the channel's protein structure, computer simulations can then be run on the protein structure to predict important parts of the channel that should be targeted during drug development. Many of the people with LQTS presently have to wear implantable defibrillators. This work therefore represents the first step towards the development of more specific therapies that may eventually free them or their children from such necessities.