Diethylstilbestrol is a potent inhibitor of store-operated channels and capacitative Ca(2+) influx.
We have recently found that diethylstilbestrol (DES), a synthetic estrogen agonist, inhibits thrombin-induced Ca(2+) influx in human platelets, but it remains unclear to what extend this effect might be related to the store-operated Ca(2+) influx pathway. To study the effect of DES on store-operated channels and capacitative Ca(2+) influx, we used rat basophilic leukemia (RBL) cells, vascular smooth muscle cells (SMC), and human platelets, and recorded whole-cell Ca(2+) release-activated Ca(2+) (CRAC) currents and thapsigargin (TG)-induced capacitative Ca(2+) influx. In this study, we demonstrate that extracellular DES produces a dose-dependent and reversible inhibition of CRAC currents in RBL cells (IC(50), approximately 0.5 microM), whereas intracellular DES (25 microM) has no effect. Extracellular DES (up to 30 microM) inhibited only CRAC but did not affect a whole-cell monovalent cation current mediated by TRPM7 channels. DES effectively inhibited TG-induced capacitative Ca(2+) influx in a dose-dependent manner with an IC(50) values of approximately 0.1 microM in RBL cells, <0.1 microM in SMC, and approximately 1 microM 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 Ca(2+) influx. Thus, we found DES to be a very effective inhibitor of store-operated channels and Ca(2+) influx in a variety of cell types.
Boston University School of Medicine, Boston, Massachusetts, USA.
Sergey I
SI
Zakharov
Tarik
T
Smani
Yuliya
Y
Dobrydneva
Francisco
F
Monje
Craig
C
Fichandler
Peter F
PF
Blackmore
Victoria M
VM
Bolotina
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D002412:Cations / Q000378:metabolism; D004054:Diethylstilbestrol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011817:Rabbits; D051381:Rats; D050053:TRPM Cation Channels
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002412:Cations; D007473:Ion Channels; D008565:Membrane Proteins; D050053:TRPM Cation Channels; D004054:Diethylstilbestrol; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; C486584:Trpm7 protein, rat; D002118:Calcium