Estrogen has numerous effects in the brain which include modulation of neurotransmitter systems and their receptors, neuroendocrine regulation, modulation of reproductive and cognitive behaviors, and neurotrophic and neuroprotective effects. It is likely that these effects involve the ability of estrogen to induce transcription of genes important in these processes. Increasing evidence is available to suggest that estrogen can promote gene transcription by signaling through pathways other than those traditionally associated with steroid hormone response element-dependent gene transcription. The estrogen receptors alpha and beta are widely and differentially distributed in the brain. Using cell culture models, we have been able to show that both receptors are capable of transducing rapid, membrane-initiated effects with reference to neuroprotection, protein phosphorylation, and gene transcription. We have provided in vivo evidence that activation of the MAP kinase pathway appears to be a prominent, initial effect of the hormone. We propose to use a combination of in vitro and in vivo approaches to further our understanding of this emerging class of steroid hormone effects. Specifically, the studies investigate differences between ERa and ER? with respect to: Mode of interaction with the cell membrane, timing of signaling events transduced, and the down-stream transcriptional responses which result from them. We will test the following Hypotheses: 1. Estrogen induces the translocation of ER?, but not ERa, to the membrane compartment of neurons to interact with other proteins. This difference results in altered kinetic characteristics in rapid signaling, and their subsequent down-stream effects on gene expression. 2. In brain regions which express ERs, E2 acts on ERa which is localized to the plasma membrane resulting in more rapid, transient changes in MARK and CREB phosphorylation than ER?. Slower, more prolonged signaling responses result from ER?, which must translocate to the membrane in order to couple with rapid signaling mechanisms. 3. In glial cells, membrane ERs couple to different cascades than in neurons, and E2 acting at ERa, but not ER?, results in a suppression of cAMP-dependent CRE-mediated gene transcription. Expression abolishes this signaling phenotype. ? ? ?
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