Stromal interaction molecule 1 (STIM1) and Orai1 mediate histamine-evoked calcium entry and NFAT signaling in human umbilical vein endothelial cells [Signal Transduction]

September 4th, 2014 by Zhou, M.–H., Zheng, H., Si, H., Jin, Y., Peng, J. M., He, L., Zhou, Y., Munoz–Garay, C., Zawieȷa, D. C., Kuo, L., Peng, X., Zhang, S. L.

Histamine is an important immunomodulator involved in allergic reactions and inflammatory responses. In endothelial cells, histamine induces Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum and eliciting Ca2+ entry across the plasma membrane. Herein, we show that histamine-evoked Ca2+ entry in human umbilical vein endothelial cells (HUVECs) is sensitive to blockers of Ca2+ release-activated Ca2+ (CRAC) channels. RNA interference against STIM1 or Orai1, the activating subunit and the pore-forming subunit of CRAC channels, respectively, abolishes this histamine-evoked Ca2+ entry. Furthermore, overexpression of dominant-negative CRAC channel subunits inhibits while co-expression of both STIM1 and Orai1 enhances histamine-induced Ca2+ influx. Interestingly, gene silencing of STIM1 or Orai1 also interrupts the activation of calcineurin/nuclear factor of activated T-cells (NFAT) pathway and the production of interleukin 8 triggered by histamine in HUVECs. Collectively, these results suggest a central role of STIM1 and Orai1 in mediating Ca2+ mobilization linked to inflammatory signaling of endothelial cells upon histamine stimulation.
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