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

Abstract

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.

Keywords: Ca(2+) signaling; ORAI inhibitor; Store-operated Ca(2+) entry; T cell activation.