Estrogen receptor (ER)alpha and ER beta exhibit unique pharmacologic properties when coupled to activation of the mitogen-activated protein kinase pathway

The rapid, nongenomic effects of estrogen are increasingly recognized as pl aying an important role in several aspects of estrogen action. Rapid activa tion of the mitogen-activated protein kinase (MAPK) signaling pathway by es trogen is among the more recently identified of these effects. To explore t he role of estrogen receptors (ERs) in mediating these effects, we have tra nsfected ER-negative Rat-2 fibroblasts with complementary DNA clones encodi ng either human ER alpha or rat ER beta and examined their ability to coupl e to activation of MAPK in response to 17 beta -estradiol (17 beta -E-2) an d other ligands. For both receptors, addition of E-2 resulted in a rapid ph osphorylation of MAPK. Activation of MAPK in ER alpha -transfected cells wa s partially and completely blocked by the antiestrogens tamoxifen and ICI 1 82,780, respectively. In ER beta -transfected cells, MAPK activation was le ss sensitive to inhibition by tamoxifen and ICI 182,780. We have also obser ved that, in this model system, a membrane-impermeable estrogen (BSA-E-2) a nd 17 alpha -E-2 were both able to activate MAPK in a manner similar to E-2 alone. Here also, ICI 182,780 blocked the ability of BSA-E-2 to activate M APK through ER alpha, but failed to block ER beta -mediated effects. BSA-E- 2 treatment, however, failed to activate nuclear estrogen-response-element- mediated gene transcription. These data show that these nuclear ERs are nec essary for estrogen's effects at the membrane. This model system will be us eful in identifying molecular interactions involved in the rapid effects me diated by the ERs.