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.