UC Davis

Potassium channels are a critical regulatory component of numerous vital cellular processes, being centrally involved in calcium signaling, membrane potential, volume regulation and action potential firing to name a few. And as such, they represent an incredibly attractive avenue for therapeutic intervention in a multitude of different diseases. KCa3.1, a calcium-activated potassium channel found throughout the peripheral tissue, serves mainly as a calcium-signaling regulator, allowing influxes of calcium through inward-rectifier calcium channels by generating a counterbalancing potassium-efflux and inducing hyperpolarizations. This calcium signaling is essential for cellular activation, production of various cytokines and the proliferation of immune cells and fibroblasts. KCa3.1 also plays an additional role in erythrocyte hydration (one of the channel’s first claims to fame) and vasodilation through endothelium-derived hyperpolarization. The related small-conductance KCa2.x channels (KCa2.1, 2.2, and 2.3) can be found alongside KCa3.1 within the peripheral tissue, but also are highly expressed throughout the CNS. KCa2.x channels help in regulating the firing rate of excitable cells, underlying the medium afterhyperpolarization of neuronal action potentials, in addition to having a prominent role in atrial repolarization. Over the course of this dissertation, we will discuss our exploration of binding sites, mechanisms of action, and selectivity of both biologics and small molecule channel modulators targeting these calcium-dependent potassium channels. By advancing our understanding of these complex interactions between protein and modulator, we hope to open up new possibilities for the design of more effective and precise therapeutic agents targeting these crucial ion channels.