Notch enhances Ca2+ entry by activating calcium-sensing receptors and inhibiting voltage-gated K+ channels

Shanshan Song, Aleksandra Babicheva, Tengteng Zhao, Ramon J. Ayon, Marisela Rodriguez, Shamin Rahimi, Francesca Balistrieri, Angela Harrington, John Y.J. Shyy, Patricia A. Thistlethwaite, Ayako Makino, Jason X.J. Yuan

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)C954-C968
JournalAmerican journal of physiology. Cell physiology
Issue number5
StatePublished - May 1 2020


  • CaSR
  • GPCR
  • KCNA5 and KCNA2
  • Notch
  • STIM2

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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    Song, S., Babicheva, A., Zhao, T., Ayon, R. J., Rodriguez, M., Rahimi, S., Balistrieri, F., Harrington, A., Shyy, J. Y. J., Thistlethwaite, P. A., Makino, A., & Yuan, J. X. J. (2020). Notch enhances Ca2+ entry by activating calcium-sensing receptors and inhibiting voltage-gated K+ channels. American journal of physiology. Cell physiology, 318(5), C954-C968.