Regulation of Voltage Gated Channels
Voltage-gated sodium channels are responsible for the action potential in excitable cells such as neuron, cardiac and skeletal muscle. We are studying the structural basis of channelopathic mutations that give rise to electrical disturbances known as arrhythmias and myotonias. By exploring the effect of the channel mutations and the corresponding protein-protein interaction, we are designing mechanistically- coherent therapies such as compensatory mutants for Brugada and long QT syndromes. For example, since Calmodulin binds the C-terminal tail of sodium and calcium voltage-gated channels, we are probing whether Brugada and long QT syndrome’ mutations reduce affinity and dislodge binding partners. We use an integrated approach from electrophysiology to structural biology in state-of-the-art disease models such as culture myocytes, myocytes derived from human iPSC cells and transgenic mice.