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Diethylstilbestrol Is a Potent Inhibitor of Store-Operated Channels and Capacitative Ca²⁺ Influx

Boston University School of Medicine, Boston, Massachusetts (S.I.Z., T.S., F.M., V.M.B.); and Eastern Virginia Medical School, Norfolk, Virginia (Y.D., C.F., P.F.B.)

We have recently found that diethylstilbestrol (DES), a synthetic estrogen agonist, inhibits thrombin-induced Ca²⁺ influx in human platelets, but it remains unclear to what extend this effect might be related to the store-operated Ca²⁺ influx pathway. To study the effect of DES on store-operated channels and capacitative Ca²⁺ influx, we used rat basophilic leukemia (RBL) cells, vascular smooth muscle cells (SMC), and human platelets, and recorded whole-cell Ca²⁺ release-activated Ca²⁺ (CRAC) currents and thapsigargin (TG)-induced capacitative Ca²⁺ influx. In this study, we demonstrate that extracellular DES produces a dose-dependent and reversible inhibition of CRAC currents in RBL cells (IC₅₀, 0.5 µM), whereas intracellular DES (25 µM) has no effect. Extracellular DES (up to 30 µM) inhibited only CRAC but did not affect a whole-cell monovalent cation current mediated by TRPM7 channels. DES effectively inhibited TG-induced capacitative Ca²⁺ influx in a dose-dependent manner with an IC₅₀ values of 0.1 µM in RBL cells, <0.1 µM in SMC, and 1 µM in human platelets. It is noteworthy that trans-stilbene, a close structural analog of DES that lacks hydroxyl and ethyl groups, had no effect on CRAC current and on store-operated Ca²⁺ influx. Thus, we found DES to be a very effective inhibitor of store-operated channels and Ca²⁺ influx in a variety of cell types.

Address correspondence to: Dr. Victoria M. Bolotina, Vascular Biology Unit, EBRC, X-704, Boston, Massachusetts, USA. E-mail: bolotina{at}bu.edu

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