Estrogen receptors (ERs) are a group of proteins found inside 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) (GPER (GPR30), ER-X, and Gq-mER), which are mostly G protein-coupled receptors. This article refers to the former (ER).
Once activated by estrogen, the ER is able to translocate into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding transcription factor). However, it also has additional functions independent of DNA binding.
As hormone receptors for sex steroids (steroid hormone receptors), ERs, androgen receptors (ARs), and progesterone receptors (PRs) are important in sexual maturation and gestation.
Proteomics
There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene ( and , respectively). Hormone-activated estrogen receptors form dimers, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers. Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains designated A/B through F (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER).
The N-terminal A/B domain is able to transactivate gene transcription in the absence of bound ligand (e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain, binds to estrogen response elements in DNA. The D domain is a hinge region that connects the C and E domains. The E domain contains the ligand binding cavity as well as binding sites for coactivator and corepressor proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.
Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERα and five ERβ isoforms have been identified. The ERβ isoforms receptor subtypes can transactivate transcription only when a heterodimer with the functional ERß1 receptor of 59 kDa is formed. The ERß3 receptor was detected at high levels in the testis. The two other ERα isoforms are 36 and 46kDa.
Only in fish, but not in humans, an ERγ receptor has been described.
Genetics
In humans, the two forms of the estrogen receptor are encoded by different genes, and on the sixth and fourteenth chromosome (6q25.1 and 14q23.2), respectively.
Distribution
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns: The ERα is found in endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. In males, ERα protein is found in the epithelium of the efferent ducts. The expression of the ERβ protein has been documented in ovarian granulosa cells, kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells. The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that only a small fraction of the ERs reside in the cytoplasm, with most ER constitutively in the nucleus. The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.
Ligands
Agonists
Endogenous estrogens (e.g., estradiol, estrone, estriol, estetrol) Natural estrogens (e.g., conjugated estrogens) Synthetic estrogens (e.g., ethinylestradiol, diethylstilbestrol)
Mixed (agonist and antagonist mode of action) Phytoestrogens (e.g., coumestrol, daidzein, genistein, miroestrol) Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)
Antagonists
Antiestrogens (e.g., fulvestrant, ICI-164384, ethamoxytriphetol)
Affinities
Binding and functional selectivity
The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.
Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor: estradiol binds equally well to both receptors estrone, and raloxifene bind preferentially to the alpha receptor estriol, and genistein to the beta receptor