Figure 2.

Overview of intracellular 17β-estradiol (E2) signaling. E2 signaling is mediated by ERs, which include two typical isoforms, ERα and ERβ. (a) Genomic signaling involves two different models occurring within hours. E2-activated dimerized ERs directly bind to nuclear ERE on the promotor of target protein regulating transcriptional responses, or modulating specific transcription factors or activator protein 1 indirectly regulating transcriptional responses. (b) Nongenomic ERs rapid signaling occurs within minutes or seconds across the plasma membrane. Member-embedded ERs or G protein-coupled ER (GPR30) are initiated by E2 and subsequently activate multiple signaling pathways, such as Src, MAPK, and AKT signaling cascades, to induce downstream ion fluxes and protein kinases activation. Mitochondria is also the target organelle of E2, where both ERα and ERβ are localized for maintaining cellular bioenergetics. Mitochondrial DNA contains ERE-like sequences, which is activated by E2-ER to regulate mitochondrial function.

ER, estrogen receptor; ERE, estrogen response element.