Functional roles of plasma membrane localized estrogen receptors

A series of emerging data supports the existence and importance of plasma membrane localized estrogen receptors in a variety of cells that are targets for the steroid hormone action. When estradiol (E2) binds to the cell surface protein, the ensuing signal transduction event triggers downstream signaling cascades that contribute to important biological functions. Aside from the classical signaling through nuclear estrogen receptors, we have provided evidence for the functional roles of an estrogen receptor localized in the plasma membrane. This review highlights some of the recent advances made in the understanding of the genomic/non-genomic actions of plasma membrane localized estrogen receptors.     

Membrane initiated estrogen signaling in breast cancer

Recent research has focused on effects of the estrogen receptor acting at the level of the cell membrane in breast cancer. In this review we describe 17beta-estradiol (E2)-initiated membrane signaling pathways involving the activation of several kinases that contribute to the regulation of cell proliferation and prevention of apoptosis. Although classical concepts had assigned priority to the nuclear actions of estrogen receptor, recent studies document the additional importance of estrogen receptor residing in or near the plasma membrane. A small fraction of estrogen receptor is associated with the cell membrane and mediates the rapid effects of E2. Unlike classical growth factor receptors, such as insulin-like growth factor 1 receptor (IGF1R) and epidermal growth factor receptor (EGFR), estrogen receptor has no transmembrane and kinase domains and is known to initiate E2 rapid signals by forming a protein complex with many signaling molecules. The formation of the protein complex is a critical step, leading to the activation of the MAPK1/3 (also known as MAP kinase) and AKT1 (also known as Akt) pathways. A full understanding of the mechanisms underlying these relationships, with the ultimate aim of abrogating specific steps, should lead to more-targeted strategies for treatment of hormone dependent-breast cancer.     

Estrogen: mechanisms for a rapid action in CA1 hippocampal neurons.

Estrogen modulates a variety of functions, most of which can be explained by the classical genomic mechanism of action. However, a number of estrogen's actions appear to be incompatible with this mechanism and fall into the category of nongenomic. In the hippocampus, application of 17beta-estradiol rapidly enhances the amplitude of kainate-induced currents of CA1 neurons. The potentiation resulted from a cyclic adenosine monophosphate-dependent phosphorylation process rather than a direct allosteric modulation of AMPA/kainate receptors. To initiate this potentiation, estrogen is required on both sides of the plasma membrane. Extracellularly, estrogen appears to activate a G-protein-coupled receptor, whereas the intracellular action of estrogen appears to be a modulation of the balance between phosphorylation and dephosphorylation. The binding sites responsible for the potentiation are genetically or pharmacologically distinct from both estrogen receptors alpha and beta. These findings provide support for the concept of a novel mechanism of action for estrogen.