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• W3012017698 abstract "The increase in cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ) and upregulation of calcium-sensing receptor (CaSR) and stromal interaction molecule 2 (STIM2) along with inhibition of voltage-gated K + (K V ) channels in pulmonary arterial smooth muscle cells (PASMC) have been implicated in the development of pulmonary arterial hypertension; however, the precise upstream mechanisms remain elusive. Activation of CaSR, a G protein-coupled receptor (GPCR), results in Ca 2+ release from the endoplasmic/sarcoplasmic reticulum (ER/SR) and Ca 2+ influx through receptor-operated and store-operated Ca 2+ channels (SOC). Upon Ca 2+ depletion from the SR, STIM forms clusters to mediate store-operated Ca 2+ entry. Activity of K V channels, like KCNA5/K V 1.5 and KCNA2/K V 1.2, contributes to regulating membrane potential, and inhibition of K V channels results in membrane depolarization that increases [Ca 2+ ] cyt by opening voltage-dependent Ca 2+ channels. In this study, we show that activation of Notch by its ligand Jag-1 promotes the clustering of STIM2, and clustered STIM2 subsequently enhances the CaSR-induced Ca 2+ influx through SOC channels. Extracellular Ca 2+ -mediated activation of CaSR increases [Ca 2+ ] cyt in CASR-transfected HEK293 cells. Treatment of CASR-transfected cells with Jag-1 further enhances CaSR-mediated increase in [Ca 2+ ] cyt . Moreover, CaSR-mediated increase in [Ca 2+ ] cyt was significantly augmented in cells co-transfected with CASR and STIM2. CaSR activation results in STIM2 clustering in CASR/STIM2-cotransfected cells. Notch activation also induces significant clustering of STIM2. Furthermore, activation of Notch attenuates whole cell K + currents in KCNA5- and KCNA2-transfected cells. Together, these results suggest that Notch activation enhances CaSR-mediated increases in [Ca 2+ ] cyt by enhancing store-operated Ca 2+ entry and inhibits KCNA5/K V 1.5 and KCNA2/K V 1.2, ultimately leading to voltage-activated Ca 2+ entry." @default.
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• W3012017698 date "2020-05-01" @default.
• W3012017698 modified "2023-10-16" @default.
• W3012017698 title "Notch enhances Ca²⁺ entry by activating calcium-sensing receptors and inhibiting voltage-gated K⁺ channels" @default.
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• W3012017698 doi "https://doi.org/10.1152/ajpcell.00487.2019" @default.
• W3012017698 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7294324" @default.
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