The Ca(2+) Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre Göttingen, Von-Siebold-Straße 3a, D-37075 Göttingen, Germany.
Biochim Biophys Acta Mol Cell Res. 2021 May;1868(6):118988. doi: 10.1016/j.bbamcr.2021.118988. Epub 2021 Feb 10.
T cell activation starts with formation of second messengers that release Ca from the endoplasmic reticulum (ER) and thereby activate store-operated Ca entry (SOCE), one of the essential signals for T cell activation. Recently, the steroidal 2-methoxyestradiol was shown to inhibit nuclear translocation of the nuclear factor of activated T cells (NFAT). We therefore investigated 2-methoxyestradiol for inhibition of Ca entry in T cells, screened a library of 2-methoxyestradiol analogues, and characterized the derivative 2-ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene (STX564) as a novel, potent and specific SOCE inhibitor. STX564 inhibits Ca entry via SOCE without affecting other ion channels and pumps involved in Ca signaling in T cells. Downstream effects such as cytokine expression and cell proliferation were also inhibited by both 2-methoxyestradiol and STX564, which has potential as a new chemical biology tool.
T 细胞的激活始于第二信使的形成，这些信使从内质网（ER）释放 Ca，从而激活储存操作的 Ca 进入（SOCE），这是 T 细胞激活的基本信号之一。最近，甾体 2-甲氧基雌二醇被证明可以抑制激活 T 细胞核因子（NFAT）的核易位。因此，我们研究了 2-甲氧基雌二醇对 T 细胞中 Ca 进入的抑制作用，筛选了 2-甲氧基雌二醇类似物文库，并将衍生物 2-乙基-3-磺酰胺氧基-17β-氰甲基雌-1,3,5(10)-三烯（STX564）表征为一种新型、有效和特异的 SOCE 抑制剂。STX564 通过 SOCE 抑制 Ca 进入，而不影响 T 细胞中参与 Ca 信号转导的其他离子通道和泵。下游效应，如细胞因子表达和细胞增殖，也被 2-甲氧基雌二醇和 STX564 抑制，这使其成为一种新的化学生物学工具。
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