2-Methoxyestradiol and its derivatives inhibit store-operated Ca2+ entry in T cells: Identification of a new and potent inhibitor

T cell activation starts with formation of second messengers that release Ca2+ from the endoplasmic reticulum (ER) and thereby activate store-operated Ca2+ entry (SOCE), one of the essential signals for T cell activation. Recently, the steroidal 2-methoxyestradiol was shown to inhibit nuclear transl...

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Published in:Biochimica et biophysica acta. Molecular cell research 2021-05, Vol.1868 (6), p.118988-118988, Article 118988
Main Authors: Löhndorf, Anke, Hosang, Leon, Dohle, Wolfgang, Odoardi, Francesca, Waschkowski, Sissy-Alina, Rosche, Anette, Bauche, Andreas, Winzer, Riekje, Tolosa, Eva, Windhorst, Sabine, Marry, Stephen, Flügel, Alexander, Potter, Barry V.L., Diercks, Björn-Philipp, Guse, Andreas H.
Format: Article
Language:English
Subjects:
Ca2+ signaling
ORAI inhibitor
Store-operated Ca2+ entry
T cell activation
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Summary:T cell activation starts with formation of second messengers that release Ca2+ from the endoplasmic reticulum (ER) and thereby activate store-operated Ca2+ 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 Ca2+ 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 Ca2+ entry via SOCE without affecting other ion channels and pumps involved in Ca2+ 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. •2-Ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene is a SOCE inhibitor.•novel inhibitor antagonizes SOCE and subsequent signaling events in different T cells•no antagonist effects on IP3 receptor, KV channels or SERCA pumps
ISSN:0167-4889
1879-2596
DOI:10.1016/j.bbamcr.2021.118988