Over 100 billion bits of information course through the brain each second, reflecting a symphony of neuronal activity governed by a large array of ion channel types in the neuronal membrane. In some instances, abnormal ion channel function leads to neurological disorders, such as tinnitus and epilepsy. In the US, nearly 25% of adults suffer from tinnitus, often described as ringing of the ears, and nearly 1% suffer from epilepsy, characterized by recurrent seizures.1 There is a significant need to develop new drug compounds to safely and specifically modulate ion channel behavior in order to treat these diseases.
This research examines the effectiveness of a novel drug compound (TS1) to treat hyperexcitability disorders like epilepsy and tinnitus by targeting KCNQ potassium ion channels. Retigabine, a previously approved KCNQ agonist, was recently removed from the market by the FDA due to adverse side effects. Our compound aims to similarly activate KCNQ channels while avoiding the harmful side effects of Retigabine.
The effectiveness of our compound is tested using whole-cell voltage clamp electrophysiology. Recordings are made from HEK293A cells stably transfected with KCNQ channels. A series of voltage steps are then applied to a single cell through an electrode. Conductance-voltage curves are generated and fit to single-component Boltzmann equations to estimate maximum conductance, half-activation voltage, and Boltzmann slope. Average results for each parameter are then compared statistically between control and various TS1 concentrations.
We expect TS1 to shift half-activation voltage to more negative potentials, enhancing channel activity and dampening overall neuronal hyperexcitability. Should we achieve the desired results, we will ultimately move to testing primary mammalian cells and conducting pre-clinical safety trials.