Stromal Interaction Molecule 1 (STIM1) and Orai1 Mediate Histamine-evoked Calcium Entry and Nuclear Factor of Activated T-cells (NFAT) Signaling in Human Umbilical Vein Endothelial Cells

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.