Subtype-Selective Positive Modulation of K Ca 2.3 Channels Increases Cilia Length.

Small-conductance Ca 2+ -activated potassium (K Ca 2.x) channels are gated exclusively by intracellular Ca 2+ . The activation of K Ca 2.3 channels induces hyperpolarization, which augments Ca 2+ signaling in endothelial cells. Cilia are specialized Ca 2+ signaling compartments. Here, we identified compound 4 that potentiates human K Ca 2.3 channels selectively. The subtype selectivity of compound 4 for human K Ca 2.3 over rat K Ca 2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of K Ca 2.3 channels by compound 4 increased flow-induced Ca 2+ signaling and cilia length, while negative modulation by AP14145 reduced flow-induced Ca 2+ signaling and cilia length. These findings were corroborated by the increased cilia length due to the expression of Ca 2+ -hypersensitive K Ca 2.3_G351D mutant channels and the reduced cilia length resulting from the expression of Ca 2+ -hyposensitive K Ca 2.3_I438N channels. Collectively, we were able to associate functions of K Ca 2.3 channels and cilia, two crucial components in the flow-induced Ca 2+ signaling of endothelial cells, with potential implications in vasodilation and ciliopathic hypertension.