Unified mechanism of Estrogen Action on central nervous system

17â-estradiol (E2)-induced neuroprotection is dependent upon both mitogen activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling cascades. We sought to determine whether E2 neuroprotective mechanisms are through a unified signaling cascade activated by estrogen receptor (ER)-PI3K interaction within the same population of neurons or whether E2 activation of ERK1/2 and Akt are independent signaling events in different neuron populations. Immunoprecipitation of E2 treated cortical neurons was conducted to determine a protein-protein interaction between ER and p85, the PI3K regulatory subunit. Subsequently, cortical neurons were treated with E2 alone or in presence of MAPK inhibitors or PI3K inhibitors. Results of these analyses indicated a protein-protein interaction between ER and p85 that was time-dependent and consistent with the temporal profile for generation of both Akt (pAkt) and ERK 1/2 phosphorylation (pERK 1/2). E2-induced phosphorylation of Akt, was first apparent at 10’ and maximal at 30’. Simultaneously, E2 induced pERK 1/2 was first apparent at 5-10’ and maximal at 30’. Inhibition of PI3K completely blocked E2 activation of pAkt at 10’ and 30’and blocked E2 activation of ERK1/2 at 10’. Double immunocytochemical labeling for pERK 1/2 and pAkt showed that E2 induced both signaling pathways in the same neurons. These results indicate a unified signaling mechanism of E2 action that is initiated by an interaction between ER and p85 and which leads to the coordinated activation of both pERK 1/2 and pAkt in the same population of neurons. These results are considered from an estrogen mechanism of action and a therapeutic development perspective.