Novel Sites and Mechanisms of Oestrogen Action in the Brain

Publisher Website
Google Scholar
Abstract
We are investigating novel, non-transcriptionally mediated mechanisms that may contribute to the differentiative effects of oestrogen in developing forebrain neurons. Recent findings in the cerebral cortex document that 17α- and 17β-oestradiol elicit rapid and sustained activation of the Ras–Raf–MAP kinase cascade, a major growth factor signalling pathway. Using oestrogen receptor (ER) α knockout (ERKO) mice, we addressed the identity of the receptor mediating activation of the MAP kinase cascade. 17β-oestradiol increased B-Raf activity and MEK-dependent ERK phosphorylation in explants of wild-type and ERKO cerebral cortex. Although neither the ERα-selective ligand, 16α-iodo-17β-oestradiol (16α-IE2) nor the ERβ-selective ligand, genistein, elicited ERK phosphorylation, as little as 0.1 nM 17β-oestradiol did so. Moreover, 16α-IE2 acted as an inhibitory modulator of ERK activation, and the ER antagonist ICI 182 780 blocked oestradiol action only in wild-type cultures. These data suggest that neither ERα nor ERβ mediate activation of the MAP kinase cascade. A putative, novel, oestradiol-sensitive and ICI 182 780-insensitive receptor, designated ER-X may, rather, be involved. Association of ER-X with flotillin, the neuronal homologue of the caveolar protein, caveolin, places ER-X within plasma membrane caveolae and supports the hypothesis that a membrane-associated ER may mediate rapid oestrogen activation of the MAP kinase cascade.

This publication has 0 references indexed in Scilit: