Multiple mechanisms associated with estrogen-dependent ER_ activation which cause a number of effects at the molecular level at different time course (Fig. 5) include: (i) estrogen binds to membrane ER_ and activates Arc expression in a rapid time-course non-genomic actions; and (ii) estrogen activates the internalization of membrane ER_ and the translocation of cytosolic ER_ to the nucleus as well as the PI-3K pathway after prolong estrogen treatment, indicating classical genomic actions. Therefore, the regulation of receptor localization is important for both classical genomic and non-genomic actions of estrogen.