Estradiol (E-2) exerts not only genotropic but also non-genomic actions through nuclear estrogen receptors (ER). Here, we provide a novel paradigm for non-genomic E-2 signaling independent of nuclear ER. E-2 induces a rapid rise in the intracellular free Ca2+ concentration ([Ca2+](i)) through membrane estrogen receptors in murine RAW 264.7 macrophages. This E-2-induced Ca2+ signaling is not prevented by different ER blockers and cannot directly activate stably transfected c-fos promoter or the mitogen-activated protein kinases p38, ERK1/2, and SAPK/JNK or NO production. However, the E-2-induced rise in [Ca2+](i) specifically down-regulates the serum-stimulated activation of c-fos promoter and ERK1/2, and conversely, it specifically up-regulates lipopolysaccharide-stimulated activation of c-fos promoter, p38, and NO production. The E-2-changed activation of c-fos promoter can be prevented by an intracellular Ca2+ chelator. Our data indicate that E-2-induced nongenomic Ca2+ signaling through membrane ER is able to specifically modulate genotropic signaling pathways with impact on macrophage activation.
