Functional and structural dynamics of KCNH4 and KCNH8

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Abstract Ion channels underlie all electrical excitability in the brain and heart, and defects in ion channels are the cause of many human disorders. The KCNH family of channels, ERG, ELK, and EAG, are voltage-dependent potassium channels that are specialized for their role in shaping the electrical activity of cells. Defects in KCNH channels have been shown to be linked to cognitive defects, increased risk of schizophrenia, cardiac arrhythmias, and cancer. Given their importance, it is surprising that some of the KCNH family members are considered “understudied”. The goal of this proposal is to study the functional and structural dynamics of the understudied KCNH4 and KCNH8 channels to lay the groundwork for future studies on the potential role of these channels in human health and disease. Previously we have performed many structural and functional experiments on KCNH and related channels and invented ground-breaking new fluorescence methods that allow us to record molecular rearrangements in intact channels simultaneous with electrophysiological recording. We propose to apply these methods to measure the functional and structural dynamics of KCNH4 and KCNH8 channels. These experiments will lead to the first dynamic picture of these understudied channels.