Estrogen receptor beta
Estrogen receptor beta (ER-), also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2), is one of two main types of estrogen receptor, a nuclear receptor which is activated by the sex hormone estrogen.  In humans, ER- is encoded by the ESR2 gene.

# Function
ER- is a member of the family of estrogen receptors and the superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17--estradiol, estriol or related ligands, the encoded protein forms homo-dimers or hetero-dimers with estrogen receptor   that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized.
ER- may have anti-proliferative effects and therefore oppose the actions of ER in reproductive tissue. ER- may also have an important role in adaptive function of the lung during pregnancy.
ER- is a potent tumor suppressor and plays a crucial role in many cancer types such as prostate cancer.

# Tissue distribution
ER- is expressed by many tissues including the uterus, blood monocytes and tissue macrophages, colonic and pulmonary epithelial cells and in prostatic epithelium and in malignant counterparts of these tissues. Also, ER- is found throughout the brain at different concentrations in different neuron clusters.

# ER- abnormalities
ER- function is related to various cardiovascular targets including ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein A1 (ApoA-1). Polymorphism may affect ER- function and lead to altered responses in postmenopausal women receiving hormone replacement therapy. Abnormalities in gene expression associated with ER- have also been linked to autism spectrum disorder.

# Disease

## Cardiovascular Disease
Mutations in ER have been shown to influence cardiomyocytes, the cells that comprise the largest part of the heart, and can lead to an increased risk of cardiovascular disease (CVD). There is a disparity in prevalence of CVD between pre- and post-menopausal women, and the difference can be attributed to estrogen levels. Many types of ER receptors exist in order to help regulate gene expression and subsequent health in the body, but binding of 17E2 (a naturally occurring estrogen) specifically improves cardiac metabolism. The heart utilizes a lot of energy in the form of ATP to properly pump blood and maintain physiological requirements in order to live, and 17E2 helps by increasing these myocardial ATP levels and respiratory function.
In addition, 17E2 can alter myocardial signaling pathways and stimulate myocyte regeneration, which can aid in inhibiting myocyte cell death. The ER signaling pathway plays a role in both vasodilation and arterial dilation, which contributes to an individual having a healthy heart rate and a decrease in blood pressure. This regulation can increase endothelial function and arterial perfusion, both of which are important to myocyte health. Thus, alterations in this signaling pathways due to ER mutation could lead to myocyte cell death from physiological stress. While ER has a more profound role in regeneration after myocyte cell death, ER can still help by increasing endothelial progenitor cell activation and subsequent cardiac function.

## Alzheimer's Disease
Genetic variation in ER is both sex and age dependent and ER polymorphism can lead to accelerated brain aging, cognitive impairment, and development of AD pathology. Similar to CVD, post-menopausal women have an increased risk of developing Alzheimers disease (AD) due to a loss of estrogen, which affects proper aging of the hippocampus, neural survival and regeneration, and amyloid metabolism. ER mRNA is highly expressed in hippocampal formation, an area of the brain that is associated with memory. This expression contributes to increased neuronal survival and helps protect against neurodegenerative diseases such as AD. The pathology of AD is also associated with accumulation of amyloid beta peptide (A). While a proper concentration of A in the brain is important for healthy functioning, too much can lead to cognitive impairment. Thus, ER helps control A levels by maintaining the protein it is derived from, -amyloid precursor protein. ER helps by up-regulating insulin-degrading enzyme (IDE), which leads to -amyloid degradation when accumulation levels begin to rise. However, in AD, lack of ER causes a decrease in this degradation and an increase in plaque build-up.
ER also plays a role in regulating APOE, a risk factor for AD that redistributes lipids across cells. APOE expression in the hippocampus is specifically regulated by 17E2, affecting learning and memory in individuals afflicted with AD. Thus, estrogen therapy via an ER-targeted approach can be used as a prevention method for AD either before or at the onset of menopause. Interactions between ER and ER can lead to antagonistic actions in the brain, so an ER-targeted approach can increase therapeutic neural responses independently of ER. Therapeutically, ER can be used in both men and women in order to regulate plaque formation in the brain.

# Neuroprotective Benefits

## Synaptic Strength and Plasticity
ER levels can dictate both synaptic strength and neuroplasticity through neural structure modifications. Variations in endogenous estrogen levels cause changes in dendritic architecture in the hippocampus, which affects neural signaling and plasticity. Specifically, lower estrogen levels lead to decreased dendritic spines and improper signaling, inhibiting plasticity of the brain. However, treatment of 17E2 can reverse this affect, giving it the ability to modify hippocampal structure. As a result of the relationship between dendritic architecture and long-term potentiation (LTP), ER can enhance LTP and lead to an increase in synaptic strength.  Furthermore, 17E2 promotes neurogenesis in developing hippocampal neurons and neurons in the subventricular zone and dentate gyrus of the adult human brain. Specifically, ER increases the proliferation of progenitor cells to create new neurons and can be increased later in life through 17E2 treatment.

# Ligands

## Agonists

### Non-selective
- Endogenous estrogens (e.g., estradiol, estrone, estriol, estetrol)
- Natural estrogens (e.g., conjugated estrogens)
- Synthetic estrogens (e.g., ethinylestradiol, diethylstilbestrol)

### Selective
Agonists of ER- selective over ER include:
- 3-Androstanediol (3-diol)  endogenous
- 8-VE2
- AC-186
- Apigenin  phytoestrogen
- Daidzein  phytoestrogen
- DCW234
- Dehydroepiandrosterone (DHEA)  endogenous
- Diarylpropionitrile (DPN)
- ERB-79 and its active enantiomer ERB-26
- ERB-196 (WAY-202196)
- Erteberel (SERBA-1, LY-500307)
- FERb 033  62-fold selectivity for ER- over ER
- Genistein  phytoestrogen; 16-fold selectivity for ER- over ER
- Kaempferol  phytoestrogen
- Liquiritigenin (Menerba)  phytoestrogen
- Penduletin  phytoestrogen
- Prinaberel (ERB-041, WAY-202041)
- S-Equol ((S)-4',7-isoflavandiol)  phytoestrogen; 13-fold selectivity for ER- over ER
- WAY-166818
- WAY-200070
- WAY-214156

## Antagonists

### Non-selective
- Selective estrogen receptor modulators (e.g., tamoxifen, raloxifene)
- Antiestrogens (e.g., fulvestrant, ICI-164384)

### Selective
Antagonists of ER- selective over ER include:
- PHTPP
- (R,R)-Tetrahydrochrysene ((R,R)-THC)  actually not selective over ER, but rather an agonist instead of antagonist of ER

# Interactions
Estrogen receptor beta has been shown to interact with:
- CCND1,
- ESR1
- MAD2L1,
- NCOA3,
- NCOA6,
- RBM39, and
- SRC.