ERβ Has Nongenomic Action in Caveolae

Abstract

ER$α$ and ER$β$ serve classically as transcription factors, and ER$α$ also mediates nongenomic responses to E2 such as the activation of endothelial nitric oxide synthase (eNOS). In contrast, the nongenomic capacities of endogenous ER$β$ are poorly understood. We evaluated eNOS activation by E2 in cultured endothelial cells that express endogenous ER$β$ to determine whether the ER$β$ isoform has nongenomic action and to reveal the subcellular locale of that function. A subpopulation of ER$β$ was localized to the endothelial cell plasma membrane, overexpression of ER$β$ enhanced rapid eNOS stimulation by E2, and the response to endogenous ER activation was inhibited by the ER$β$-selective antagonist RR-tetrahydrochrysene (THC). eNOS activation through ER$β$ was reconstituted and shown to occur independent of ER$α$ in COS-7 cells, and ER$β$ protein in COS-7 was directed to the plasma membrane. THC also blunted E2 activation of eNOS in isolated endothelial cell plasma membranes. Furthermore, ER$β$ protein was detected and THC attenua...