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Rapid, nonclassical 17β-estradiol (E2) actions are thought to play an important role in the modulation of neuronal function. The present study addresses the intracellular signaling cascades involved in the rapid E2-induced phosphorylation of cAMP response element binding protein (CREB) in GnRH neurons. Administration of E2 to adult female mice resulted in the activation of ERK1/2 in GnRH neurons within 15 min. In vitro studies using pharmacological antagonists showed that ERK1/2 was essential for E2-induced CREB phosphorylation in GnRH neurons. Upstream to this, protein kinase A and calcium/calmodulin-dependent protein kinase type II, but not protein kinase C, were found to be necessary for E2-induced phosphorylation of ERK1/2. This rapid E2 signaling cascade in GnRH neurons was found to require both direct and indirect E2 actions. E2 failed to phosphorylate ERK1/2 and CREB in GnRH neuron …