Subtype-Selective Positive Modulation of K_Ca2.3 Channels Increases Cilia Length

Authors

Young-Woo Nam, Chapman University
Rajasekharreddy Pala, Chapman UniversityFollow
Naglaa Salem El-Sayed, Chapman UniversityFollow
Denisse Laren-Henriquez, Chapman University
Farideh Amirrad, Chapman UniversityFollow
Grace Yang, Chapman University
Mohammad Asikur Rahman, Chapman University
Razan Orfali, Chapman UniversityFollow
Myles Downey, Chapman University
Keykavous Parang, Chapman UniversityFollow
Surya M. Nauli, Chapman UniversityFollow
Miao Zhang, Chapman UniversityFollow

Document Type

Article

Publication Date

8-10-2022

Abstract

Small-conductance Ca²⁺-activated potassium (K_Ca2.x) channels are gated exclusively by intracellular Ca²⁺. The activation of K_Ca2.3 channels induces hyperpolarization, which augments Ca²⁺ signaling in endothelial cells. Cilia are specialized Ca²⁺ signaling compartments. Here, we identified compound 4 that potentiates human K_Ca2.3 channels selectively. The subtype selectivity of compound 4 for human K_Ca2.3 over rat K_Ca2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of K_Ca2.3 channels by compound 4 increased flow-induced Ca²⁺ signaling and cilia length, while negative modulation by AP14145 reduced flow-induced Ca²⁺ signaling and cilia length. These findings were corroborated by the increased cilia length due to the expression of Ca²⁺-hypersensitive K_Ca2.3_G351D mutant channels and the reduced cilia length resulting from the expression of Ca²⁺-hyposensitive K_Ca2.3_I438N channels. Collectively, we were able to associate functions of K_Ca2.3 channels and cilia, two crucial components in the flow-induced Ca²⁺ signaling of endothelial cells, with potential implications in vasodilation and ciliopathic hypertension.

Comments

This article was originally published in ACS Chemical Biology in 2022. https://doi.org/10.1021/acschembio.2c00469

Recommended Citation

Nam Y-W, Pala R, El-Sayed NS, et al. Subtype-selective positive modulation of K_Ca2.3 channels increases cilia length. ACS Chem. Biol.. 2022. https://doi.org/10.1021/acschembio.2c00469

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This work is licensed under a Creative Commons Attribution 4.0 License.