Estrogen Receptor/ERR

Estrogen receptors (ERs) are a group of proteins found inside and on cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors.

Raloxifene HCl
Y 134
Toremifene citrate
MPP dihydrochloride
Estradiol valerate


Nuclear Estrogen Receptors (ERs) are transcription factors that regulate target genes involved in metabolism, development, reproduction, and homeostasis. The natural ligand for ERs is Ea, which, due to its lipophyiic nature, freely diffuses through membranes where it binds to ERs, dissociating the ERs from heat shock proteins. Once bound by E2, the ERs dimerize, interact with various co-activator and co-repressor proteins, and bind to regulatory elements in the promoters of genes to control transcription.

Certain pesticides, surfactants, plasticizers, pharmaceuticals, and phytoestrogens have been shown to bind to and activate estrogen receptors in vitro, thereby acting as endogenous E2. Furthermore exposure to these compounds in vivo has resulted in induction of genes known to be regulated by ERs, including those involved in egg formation in oviparous species, transcription factors such as c-fos, c-myc, and c-jun, progesterone receptor, pS2, cathepsin D, aspartic protease, and the ERs themselves. With the recent advances in gene array technology, many transcripts shown to be altered by E2 and xenoestrogens are continually being added to this list.

Until 1996 it was believed that one ER was responsible for mediating E2 regulated functions. This ER, now termed ER alpha, had been shown to bind E2 and direct gene expression through direct DNA binding. A decade after the initial cloning of ER alpha, was cloned from rat tissues, and has since been identified in several species including humans and fish. The beta receptor was determined to be a distinct form, encoded by a separate gene. Even more surprising was the recent identification of a third ER (gamma), in the fish Atlantic croaker. No reports indicate the existence of this isotype in mammals to date. The discovery of multiple ER isotypes further increase the complexity of the molecular mechanisms involved in the transcriptional regulation of genes via the ER pathway.

Although ERs are classically thought of as nuclear transcription factors, it is becoming more widely accepted that membrane bound forms exist. Membrane ERs (mERs) are G-protein coupled receptors that mediate rapid non-genomic actions of E2. The first evidence of mERs was reported in 1977 when it was discovered that E2 rapidly increased intracellular cAMP. At the time it was hypothesized that this rapid signaling event was occurring via ERs in the plasma membrane. It wasn’t until the early 1990s that additional scientific evidence supported this idea. Key experiments revealed that E2 was able to stimulate signaling molecules such as mitogenactivated protein kinase (MAPK), protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and phosphoinositide-3 kinase (PI3K) despite its inability to pass through the plasma membrane since it was covalently linked to BSA. Other studies have detected ERs in the plasma membrane with antibodies raised against the nuclear forms in several cell types, suggesting the nuclear and membrane forms are similar. These results have been seen in both mammals and fish suggesting the presence of mERs are conserved across species.

The biological functions of mERs are not completely known but have been implicated in the regulation of cell growth and survival, migration, new blood vessel formation, prevention of the inflammatory response to muscle injury, and maintenance of endothelial cell cytoskeleton. There is evidence to suggest that the mERs and nuclear ERs are complimentary, where transcription activated by rapid signaling is sustained by nuclear ERs. Since the quantity of mERs in the plasma membrane account for only a small portion of the total ERs in a cell, mERs are possibly a subset of nuclear ERs that somehow are targeted to the cell surface. One report indicates that a specific serine residue (S522 in the human ER alpha) is important for the interaction of the mERs with calveolin, a scaffolding protein that brings together signaling molecules in discrete areas of the plasma membrane. Overall, the existence of mERs further complicates our understanding of the regulation of cellular processes by E2.