Notch enhances Ca2+ entry by activating calcium-sensing receptors and inhibiting voltage-gated K+ channels
| العنوان: | Notch enhances Ca2+ entry by activating calcium-sensing receptors and inhibiting voltage-gated K+ channels |
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| المؤلفون: | Shamin Rahimi, Tengteng Zhao, Ayako Makino, Marisela Rodriguez, Angela Harrington, Shanshan Song, Patricia A. Thistlethwaite, Aleksandra Babicheva, Ramon J. Ayon, Francesca Balistrieri, John Y.-J. Shyy, Jason X.-J. Yuan |
| المصدر: | American Journal of Physiology-Cell Physiology. 318:C954-C968 |
| بيانات النشر: | American Physiological Society, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Membrane potential, SOC channels, Stromal Interaction Molecule 2, Physiology, Chemistry, Endoplasmic reticulum, Depolarization, Cell Biology, STIM2, 030204 cardiovascular system & hematology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Biophysics, Receptor, G protein-coupled receptor |
| الوصف: | The increase in cytosolic Ca2+ concentration ([Ca2+]cyt) and upregulation of calcium-sensing receptor (CaSR) and stromal interaction molecule 2 (STIM2) along with inhibition of voltage-gated K+ (KV) 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 Ca2+ release from the endoplasmic/sarcoplasmic reticulum (ER/SR) and Ca2+ influx through receptor-operated and store-operated Ca2+ channels (SOC). Upon Ca2+ depletion from the SR, STIM forms clusters to mediate store-operated Ca2+ entry. Activity of KV channels, like KCNA5/KV1.5 and KCNA2/KV1.2, contributes to regulating membrane potential, and inhibition of KV channels results in membrane depolarization that increases [Ca2+]cyt by opening voltage-dependent Ca2+ 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 Ca2+ influx through SOC channels. Extracellular Ca2+-mediated activation of CaSR increases [Ca2+]cyt in CASR-transfected HEK293 cells. Treatment of CASR-transfected cells with Jag-1 further enhances CaSR-mediated increase in [Ca2+]cyt. Moreover, CaSR-mediated increase in [Ca2+]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 [Ca2+]cyt by enhancing store-operated Ca2+ entry and inhibits KCNA5/KV1.5 and KCNA2/KV1.2, ultimately leading to voltage-activated Ca2+ entry. |
| تدمد: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00487.2019 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::9c18cc62f8e857b3a055830db6c5f093 https://doi.org/10.1152/ajpcell.00487.2019 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........9c18cc62f8e857b3a055830db6c5f093 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15221563 03636143 |
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| DOI: | 10.1152/ajpcell.00487.2019 |