Zhou Meng-Hua, Zheng Hongying, Si Hongjiang, Jin Yixin, Peng Jasmine M, He Lian, Zhou Yubin, Muñoz-Garay Carlos, Zawieja David C, Kuo Lih, Peng Xu, Zhang Shenyuan L
From the Departments of Medical Physiology and.
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
J Biol Chem. 2014 Oct 17;289(42):29446-56. doi: 10.1074/jbc.M114.578492. Epub 2014 Sep 4.
Histamine is an important immunomodulator involved in allergic reactions and inflammatory responses. In endothelial cells, histamine induces Ca(2+) mobilization by releasing Ca(2+) from the endoplasmic reticulum and eliciting Ca(2+) entry across the plasma membrane. Herein, we show that histamine-evoked Ca(2+) entry in human umbilical vein endothelial cells (HUVECs) is sensitive to blockers of Ca(2+) release-activated Ca(2+) (CRAC) channels. RNA interference against STIM1 or Orai1, the activating subunit and the pore-forming subunit of CRAC channels, respectively, abolishes this histamine-evoked Ca(2+) entry. Furthermore, overexpression of dominant-negative CRAC channel subunits inhibits while co-expression of both STIM1 and Orai1 enhances histamine-induced Ca(2+) 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 Ca(2+) mobilization linked to inflammatory signaling of endothelial cells upon histamine stimulation.
组胺是一种参与过敏反应和炎症反应的重要免疫调节剂。在内皮细胞中，组胺通过从内质网释放Ca(2+)并引发Ca(2+)跨质膜内流来诱导Ca(2+)动员。在此，我们表明组胺诱发的人脐静脉内皮细胞（HUVECs）中的Ca(2+)内流对Ca(2+)释放激活的Ca(2+)（CRAC）通道阻滞剂敏感。分别针对CRAC通道的激活亚基STIM1或孔形成亚基Orai1进行RNA干扰，可消除这种组胺诱发的Ca(2+)内流。此外，显性负性CRAC通道亚基的过表达会抑制组胺诱导的Ca(2+)内流，而STIM1和Orai1的共表达则会增强组胺诱导的Ca(2+)内流。有趣的是，STIM1或Orai1的基因沉默也会中断HUVECs中由组胺触发的钙调神经磷酸酶/活化T细胞核因子（NFAT）途径的激活以及白细胞介素8的产生。总体而言，这些结果表明STIM1和Orai1在介导组胺刺激后与内皮细胞炎症信号相关的Ca(2+)动员中起核心作用。
