Modulation of αCaMKII signaling by rapid ERα action

The estrogen receptor (ER) subtypes, ER alpha and ER beta modulate numerous signaling cascades in the brain to result in a variety of cell fates including neuronal differentiation. We report here that 17 beta-estradiol (E2) rapidly stimulates the autophosphorylation of alpha-Ca2+/calmodulin-dependent kinase II (alpha CaMKII) in immortalized NLT GnRH neurons, primary hippocampal neurons, and Cos7 cells co-transfected with ER alpha and alpha CaMKII. The E2-induced alpha CaMKII autophosphorylation is ER alpha- and Ca2+/calmodulin (CaM)-dependent. Interestingly, the hormone-dependent association of ER alpha with aCaMKII attenuates the positive effect of E2 on alpha CaMKII autophosphorylation, suggesting that ER alpha plays a complex role in modulating alpha CaMKII activity and may function to fine-tune alpha CaMKII-triggered signaling events. However, it appears as though the activating signal of E2 dominates the negative effect of ER since there is a clear, positive downstream response to E2-activated alpha CaMKII; pharmacological inhibitors and RNAi technology show that targets of ER alpha-mediated alpha CaMKII signaling include extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP response element-binding protein (CREB), and microtubule associated protein 2 (MAP2). These findings suggest a novel model for the modulation of alpha CaMKII signaling by ER alpha, which provides a molecular link as to how E2 might influence brain function. (C) 2008 Elsevier B.V. All rights reserved.