17‐β‐Estradiol‐mediated activation of extracellular‐signal regulated kinase, phosphatidylinositol 3‐kinase/protein kinase B‐Akt and N‐methyl‐d‐aspartate receptor phosphorylation in cortical synaptoneurosomes

Abstract

In addition to its well‐known activational mechanism, the steroid hormone 17‐β‐estradiol (E2) has been shown to rapidly activate various signal transduction pathways that could participate in estrogen‐mediated regulation of synaptic plasticity. Although the mechanisms underlying these effects are not clearly understood, it has been repeatedly suggested that they involve a plasma membrane receptor which has direct links to several intracellular signaling cascades. To further address the question of whether E2 acts directly at the synapse and through membrane‐bound receptors, we studied the effects of E2 and of ligands of estrogen receptors on various signaling pathways in cortical synaptoneurosomes. Our results demonstrate that E2 elicits N‐methyl‐d‐aspartate receptor phosphorylation and activates the extracellular signal‐regulated kinase and the phosphatidylinositol 3‐kinase/Akt signal transduction pathways in this cortical membrane preparation. Furthermore, we provide evidence for the presence of a membrane‐bound estrogen receptor responsible for these effects in cortical synaptoneurosomes. Our study demonstrates that E2 directly acts at cortical synapses, and that synaptoneurosomes provide a useful system to investigate the mechanisms by which E2 regulates synaptic transmission and plasticity.