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Estradiol (E₂) exerts not only genotropic but also nongenomic actions through nuclear estrogen receptors (ER). Here, we provide a novel paradigm for nongenomic E₂ signaling independent of nuclear ER. E₂induces a rapid rise in the intracellular free Ca²⁺concentration ([Ca²⁺] _i) through membrane estrogen receptors in murine RAW 264.7 macrophages. This E₂-induced Ca²⁺ signaling is not prevented by different ER blockers and cannot directly activate stably transfected c-fospromoter or the mitogen-activated protein kinases p38, ERK1/2, and SAPK/JNK, or NO production. However, the E₂-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 E₂-changed activation of c-fos promoter can be prevented by an intracellular …