Plasma Membrane Estrogen Receptors Exist and Functions as Dimers

A small pool of estrogen receptors (ERα and -β) localize at the plasma membrane and rapidly signal to affect cellular physiology. Although nuclear ERs function mainly as homodimers, it is unknown whether membrane-localized ER exists or functions with similar requirements. We report that the endogenous ER isoforms at the plasma membrane of breast cancer or endothelial cells exist predominantly as homodimers in the presence of 17β-estradiol (E2). Interestingly, in endothelial cells made from ERα /ERβ homozygous double-knockout mice, membrane ERα or ERβ are absent, indicating that the endogenous membrane receptors derive from the same gene(s) as the nuclear receptors. In ER-negative breast cancer cells or Chinese hamster ovary cells, we expressed and compared wild-type and dimer mutant mouse ERα. Only wild-type ERα supported the ability of E2 to rapidly activate ERK, cAMP, and phosphatidylinositol 3-kinase signaling. This resulted from E2 activating Gsα and Gqα at the membrane in cells expressing the wild-type, but not the dimer mutant, ERα. Intact, but not dimer mutant, ERα also supported E2-induced epidermal growth factor receptor transactivation and cell survival. We also confirmed the requirement of dimerization for membrane ER function using a second, less extensively mutated, human ERα. In summary, endogenous membrane ERs exist as dimers, a structural requirement that supports rapid signal transduction and affects cell physiology.