Subtype-Selective Positive Modulation of K2.3 Channels Increases Cilia Length.

Small-conductance Ca-activated potassium (K2.x) channels are gated exclusively by intracellular Ca. The activation of K2.3 channels induces hyperpolarization, which augments Ca signaling in endothelial cells. Cilia are specialized Ca signaling compartments. Here, we identified compound that potentiates human K2.3 channels selectively. The subtype selectivity of compound for human K2.3 over rat K2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of K2.3 channels by compound increased flow-induced Ca signaling and cilia length, while negative modulation by AP14145 reduced flow-induced Ca signaling and cilia length. These findings were corroborated by the increased cilia length due to the expression of Ca-hypersensitive K2.3_G351D mutant channels and the reduced cilia length resulting from the expression of Ca-hyposensitive K2.3_I438N channels. Collectively, we were able to associate functions of K2.3 channels and cilia, two crucial components in the flow-induced Ca signaling of endothelial cells, with potential implications in vasodilation and ciliopathic hypertension.