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Orthologs
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Estrogen receptor beta (ER-β), 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.[1] In humans, ER-β is encoded by the ESR2 gene.[2]

Function

ER-β 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-β-estradiol, estriol or related ligands, the encoded protein forms homo-dimers or hetero-dimers with estrogen receptor α 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.[3]

ER-β may have anti-proliferative effects and therefore oppose the actions of ERα in reproductive tissue.[4] ER-β may also have an important role in adaptive function of the lung during pregnancy.[5]

ER-β is a potent tumor suppressor and plays a crucial role in many cancer types such as prostate cancer.[6][7]

Tissue distribution

ER-β is expressed by many tissues including the uterus,[8] blood monocytes and tissue macrophages, colonic and pulmonary epithelial cells and in prostatic epithelium and in malignant counterparts of these tissues. Also, ER-β is found throughout the brain at different concentrations in different neuron clusters.[9][10]

ER-β abnormalities

ER-β function is related to various cardiovascular targets including ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein A1 (ApoA-1). Polymorphism may affect ER-β function and lead to altered responses in postmenopausal women receiving hormone replacement therapy. [11] Abnormalities in gene expression associated with ER-β have also been linked to autism spectrum disorder. [12]

Disease

Cardiovascular Disease

Mutations in ERβ 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 ERβ receptors exist in order to help regulate gene expression and subsequent health in the body, but binding of 17βE2 (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 17βE2 helps by increasing these myocardial ATP levels and respiratory function[13].

In addition, 17βE2 can alter myocardial signaling pathways and stimulate myocyte regeneration, which can aid in inhibiting myocyte cell death. The ERβ 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 ERβ mutation could lead to myocyte cell death from physiological stress. While ERα has a more profound role in regeneration after myocyte cell death, ERβ can still help by increasing endothelial progenitor cell activation and subsequent cardiac function[14].

Alzheimer's Disease

Genetic variation in ERβ is both sex and age dependent and ERβ 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 Alzheimer’s disease (AD) due to a loss of estrogen, which affects proper aging of the hippocampus, neural survival and regeneration, and amyloid metabolism. ERβ 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 (Aβ). While a proper concentration of Aβ in the brain is important for healthy functioning, too much can lead to cognitive impairment. Thus, ERβ helps control Aβ levels by maintaining the protein it is derived from, β-amyloid precursor protein. ERβ helps by up-regulating insulin-degrading enzyme (IDE), which leads to β-amyloid degradation when accumulation levels begin to rise. However, in AD, lack of ERβ causes a decrease in this degradation and an increase in plaque build-up[15].

ERβ 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 17βE2, affecting learning and memory in individuals afflicted with AD. Thus, estrogen therapy via an ERβ-targeted approach can be used as a prevention method for AD either before or at the onset of menopause. Interactions between ERα and ERβ can lead to antagonistic actions in the brain, so an ERβ-targeted approach can increase therapeutic neural responses independently of ERα. Therapeutically, ERβ can be used in both men and women in order to regulate plaque formation in the brain[16].

Neuroprotective Benefits

Synaptic Strength and Plasticity

ERβ 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 17βE2 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), ERβ can enhance LTP and lead to an increase in synaptic strength. Furthermore, 17βE2 promotes neurogenesis in developing hippocampal neurons and neurons in the subventricular zone and dentate gyrus of the adult human brain. Specifically, ERβ increases the proliferation of progenitor cells to create new neurons and can be increased later in life through 17βE2 treatment[17][18].

Ligands

Agonists

Non-selective

Selective

Agonists of ER-β selective over ERα include:

Antagonists

Non-selective

Selective

Antagonists of ER-β selective over ERα include:

Interactions

Estrogen receptor beta has been shown to interact with:

References

  1. ↑ Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (June 1996). "Cloning of a novel receptor expressed in rat prostate and ovary". Proc. Natl. Acad. Sci. U.S.A. 93 (12): 5925–30. doi:10.1073/pnas.93.12.5925. PMC 39164. PMID 8650195.
  2. ↑ Mosselman S, Polman J, Dijkema R (August 1996). "ER beta: identification and characterization of a novel human estrogen receptor". FEBS Lett. 392 (1): 49–53. doi:10.1016/0014-5793(96)00782-X. PMID 8769313.
  3. ↑ "Entrez Gene: ESR2 estrogen receptor 2 (ER beta)".
  4. ↑ Weihua Z, Saji S, Mäkinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA (2000). "Estrogen receptor (ER) β, a modulator of ERα in the uterus". Proc. Natl. Acad. Sci. U.S.A. 97 (11): 5936–41. doi:10.1073/pnas.97.11.5936. PMC 18537. PMID 10823946.
  5. ↑ Carey MA, Card JW, Voltz JW, Germolec DR, Korach KS, Zeldin DC (2007). "The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies". Am. J. Physiol. Lung Cell Mol. Physiol. 293 (2): L272–8. doi:10.1152/ajplung.00174.2007. PMID 17575008.
  6. ↑ Stettner M, Kaulfuss S, Burfeind P, Schweyer S, Strauss A, Ringert RH, Thelen P (2007). "The relevance of estrogen receptor-beta expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment". Mol Cancer Ther. 6 (10): 2626–33. doi:10.1158/1535-7163.MCT-07-0197. PMID 17913855.
  7. ↑ Kyriakidis I, Papaioannidou P (June 2016). "Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy". Arch Gynecol Obstet. 293 (6): 1161–8. doi:10.1007/s00404-016-4027-8. PMID 26861465.
  8. ↑ Hapangama DK, Kamal AM, Bulmer JN (Mar 2015). "Estrogen receptor β: the guardian of the endometrium". Human Reproduction Update. 21 (2): 174–193. doi:10.1093/humupd/dmu053. PMID 25305176.
  9. ↑ Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS (1997). "Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERα) and estrogen receptor-beta (ER-β) messenger ribonucleic acid in the wild-type and ERα-knockout mouse". Endocrinology. 138 (11): 4613–21. doi:10.1210/en.138.11.4613. PMID 9348186.
  10. ↑ Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA (2005). "Reflections on the discovery and significance of estrogen receptor β". Endocr. Rev. 26 (3): 465–78. doi:10.1210/er.2004-0027. PMID 15857973.
  11. ↑ Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (January–February 2011). "Effect of estrogen receptor beta A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy". Genetic testing and molecular biomarkers. 15 (1–2): 11–15. doi:10.1089/gtmb.2010.0106. PMID 21117950.
  12. ↑ Crider A, Thakkar R, Ahmed A, Pillai A (9 September 2014). "Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects". Molecular Autism. 5 (46). doi:10.1186/2040-2392-5-46.
  13. ↑ Luo, Tao; Kim, Jin Kyung (August 2016). "The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview". The Canadian Journal of Cardiology. 32 (8): 1017–1025. doi:10.1016/j.cjca.2015.10.021. ISSN 1916-7075. PMC 4853290. PMID 26860777.
  14. ↑ Muka, Taulant; Vargas, Kris G.; Jaspers, Loes; Wen, Ke-xin; Dhana, Klodian; Vitezova, Anna; Nano, Jana; Brahimaj, Adela; Colpani, Veronica (April 2016). "Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies". Maturitas. 86: 28–43. doi:10.1016/j.maturitas.2016.01.009. ISSN 1873-4111. PMID 26921926.
  15. ↑ Li, Rena; Cui, Jie; Shen, Yong (2014-05-25). "Brain sex matters: estrogen in cognition and Alzheimer's disease". Molecular and Cellular Endocrinology. 389 (1–2): 13–21. doi:10.1016/j.mce.2013.12.018. ISSN 1872-8057. PMC 4040318. PMID 24418360.
  16. ↑ Zhao, Liqin; Woody, Sarah K.; Chhibber, Anindit (November 2015). "Estrogen receptor β in Alzheimer's disease: From mechanisms to therapeutics". Ageing Research Reviews. 24 (Pt B): 178–190. doi:10.1016/j.arr.2015.08.001. ISSN 1872-9649. PMC 4661108. PMID 26307455.
  17. ↑ Engler-Chiurazzi, E.B.; Brown, C.M.; Povroznik, J.M.; Simpkins, J.W. "Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury". Progress in Neurobiology. 157: 188–211. doi:10.1016/j.pneurobio.2015.12.008.
  18. ↑ Vargas, Kris G.; Milic, Jelena; Zaciragic, Asija; Wen, Ke-Xin; Jaspers, Loes; Nano, Jana; Dhana, Klodian; Bramer, Wichor M.; Kraja, Bledar (November 2016). "The functions of estrogen receptor beta in the female brain: A systematic review". Maturitas. 93: 41–57. doi:10.1016/j.maturitas.2016.05.014. ISSN 1873-4111. PMID 27338976.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 Hajirahimkhan A, Dietz BM, Bolton JL (May 2013). "Botanical modulation of menopausal symptoms: mechanisms of action?". Planta Medica. 79 (7): 538–53. doi:10.1055/s-0032-1328187. PMC 3800090. PMID 23408273.
  20. ↑ Minutolo F, Bertini S, Granchi C, Marchitiello T, Prota G, Rapposelli S, Tuccinardi T, Martinelli A, Gunther JR, Carlson KE, Katzenellenbogen JA, Macchia M (2009). "Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta". J. Med. Chem. 52 (3): 858–67. doi:10.1021/jm801458t. PMID 19128016.
  21. ↑ Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S (1998). "Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists". Mol. Pharmacol. 54 (1): 105–12. PMID 9658195.
  22. ↑ Nakamura Y, Felizola SJ, Kurotaki Y, Fujishima F, McNamara KM, Suzuki T, Arai Y, Sasano H (May 2013). "Cyclin D1 (CCND1) expression is involved in estrogen receptor beta (ER-β) in human prostate cancer". Prostate. 73 (6): 590–5. doi:10.1002/pros.22599. PMID 23060014.
  23. ↑ Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (February 1998). "The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro". Biochem. Biophys. Res. Commun. 243 (1): 122–6. doi:10.1006/bbrc.1997.7893. PMID 9473491.
  24. ↑ 24.0 24.1 Poelzl G, Kasai Y, Mochizuki N, Shaul PW, Brown M, Mendelsohn ME (March 2000). "Specific association of estrogen receptor β with the cell cycle spindle assembly checkpoint protein, MAD2". Proc. Natl. Acad. Sci. U.S.A. 97 (6): 2836–9. doi:10.1073/pnas.050580997. PMC 16016. PMID 10706629.
  25. ↑ Wong CW, Komm B, Cheskis BJ (June 2001). "Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands". Biochemistry. 40 (23): 6756–65. doi:10.1021/bi010379h. PMID 11389589.
  26. ↑ Leo C, Li H, Chen JD (February 2000). "Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3". J. Biol. Chem. 275 (8): 5976–82. doi:10.1074/jbc.275.8.5976. PMID 10681591.
  27. ↑ Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW (February 2001). "Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2". Mol. Endocrinol. 15 (2): 241–54. doi:10.1210/me.15.2.241. PMID 11158331.
  28. ↑ Ko L, Cardona GR, Iwasaki T, Bramlett KS, Burris TP, Chin WW (January 2002). "Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs". Mol. Endocrinol. 16 (1): 128–40. doi:10.1210/mend.16.1.0755. PMID 11773444.
  29. ↑ Jung DJ, Na SY, Na DS, Lee JW (January 2002). "Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors". J. Biol. Chem. 277 (2): 1229–34. doi:10.1074/jbc.M110417200. PMID 11704680.
  30. ↑ Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F (October 2000). "Steroid-induced androgen receptor–oestradiol receptor β–Src complex triggers prostate cancer cell proliferation". EMBO J. 19 (20): 5406–17. doi:10.1093/emboj/19.20.5406. PMC 314017. PMID 11032808.
  31. ↑ Slentz-Kesler K, Moore JT, Lombard M, Zhang J, Hollingsworth R, Weiner MP (October 2000). "Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta". Genomics. 69 (1): 63–71. doi:10.1006/geno.2000.6299. PMID 11013076.

Further reading

External links

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