FIGURE 4.

Nongenomic estrogen-initiated signal transduction leading to spinogenesis and changes in synapse size. Estrogen initiates a complex set of signal transduction pathways in the hippocampal neuron via membrane-bound estrogen receptors. Rapid activation of Akt (protein kinase B) via PI3K is mediated by ER α. Subsequently, activated Akt initiates translation of PSD-95 by disinhibiting the initiation factor 4E-binding protein 1 (4E-BP1). Estradiol-mediated phosphorylation of cofilin occurs via activation of LIMK. Cofilin depolymerizes actin and is inactivated by phosphorylation. Therefore, in the presence of estrogen, cofilin repression of actin polymerization is removed, resulting in an increase in filopodial density. The signal transduction pathways illustrated here are an oversimplification of a large body of work performed in an in vitro cell line.