Extranuclear Signaling Effects Mediated by the Estrogen Receptor; Annual summary rept. 15 Feb 2005-14 Feb 2008

摘要

The ER modulates various signaling cascades involved in the survival and differentiation of a wide range of tissues, both reproductive and nonreproductive. In our studies, we confirmed that 17 -estradiol (E2) and other ER-specific ligands rapidly phosphorylate ERK1/2 in breast cancer and neuronal cell lines. Subsequently, we found that E2 rapidly stimulates aCaMKII autophosphorylation in immortalized GnRH neurons and primary hippocampal neurons in a calmodulin and Ca2+ influx-dependent manner. Interestingly, ERa associates with aCaMKII and their interaction attenuates the positive effect of E2 on aCaMKII autophosphorylation, suggesting that ERa plays a complex role in modulating aCaMKII activity. However, it appears that the activating signal of E2 is dominant since there is a clear, positive downstream response to E2- activated aCaMKII; pharmacological inhibitors and RNAi technology demonstrated ERa-mediated aCaMKII signaling targets ERK1/2, CREB, and MAP2 for phosphorylation. In vivo, E2 or PPT administration to ovariectomized female rats significantly enhances aCaMKII activity in the hippocampus after 1 hr or 24 hr of exposure. Additionally, E2 administration induces ERK1/2 phosphorylation in vivo in the uterine horn and brain extracts. Functionally, E2-induced aCaMKII signaling influences neurite outgrowth of primary hippocampal neurons. Our findings suggest a novel model for the modulation of aCaMKII signaling by ERa, which provides a molecular link as to how E2 might influence brain function. Ultimately, the characterization of this signaling pathway could be exploited to create new selective estrogen receptor modulators that enhance cognitive function in postmenopausal women without affecting breast tissue or increasing the risk of developing breast cancer.