Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Epilepsy is a common disease affecting roughly 1% of the worldwide population. However, 30% of epileptic patients are unresponsive to the numerous anti-epileptic drugs that are available, highlighting the need for more effective therapies. The discovery of the anti-convulsant retigabine supports the notion that in order to achieve this, novel drug targets must be explored. Retigabine is unlike any other existing anti-epileptic drug in that it reduces seizure frequency by opening voltage-gated KCNQ potassium channels in the brain. By acting through a new mode of action, it has been shown in clinical trials to prevent seizures in many patients who were refractory to pre-existing therapies. As a 'first-in-class' drug, investigating the detailed mechanisms of retigabine has the potential to open doors for the development of more effective channel openers not only for the treatment of epilepsy but also for other conditions involving excitability such as pain and migraines. For my doctoral work I will use a technique called Unnatural Amino Acid Mutagenesis to engineer the retigabine binding site of KCNQ channels in order to determine the detailed chemical interactions that are essential for retigabine's effects. By elucidating the specific components of the retigabine molecule that interact with the channel protein and the underlying forces that mediate drug binding, these studies will offer insights into how the structure of retigabine can be modified in order to develop drugs with safer and more selective profiles. Furthermore, I will use a technique called Voltage Clamp Fluorometry to investigate how retigabine binding leads to KCNQ channel opening. This method will allow us to use retigabine as a tool to understand how KCNQ channels respond to changes in membrane voltage to help regulate neuronal excitability, and provide insights that will be broadly applicable to other related ion channels and diseases.