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Estrogen Receptors in Cell Membranes: Regulation and Signaling

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Transport Across Natural and Modified Biological Membranes and its Implications in Physiology and Therapy

Part of the book series: Advances in Anatomy, Embryology and Cell Biology ((ADVSANAT,volume 227))

Abstract

Estrogens can stimulate the development, proliferation, migration, and survival of target cells. These biological effects are mediated through their action upon the plasma membrane estrogen receptors (ERs). ERs regulate transcriptional processes by nuclear translocation and binding to specific response elements, which leads to the regulation of gene expression. This effect is termed genomic or nuclear. However, estrogens may exert their biological activity also without direct binding to DNA and independently of gene transcription or protein synthesis. This action is called non-genomic or non-nuclear. Through non-genomic mechanisms, estrogens can modify regulatory cascades such as MAPK, P13K, and tyrosine cascade as well as membrane-associated molecules such as ion channels and G-protein-coupled receptors. The recent studies on the mechanisms of estrogen action provide an evidence that non-genomic and genomic effects converge. An example of such convergence is the potential possibility to modulate gene expression through these two independent pathways. The understanding of the plasma membrane estrogen receptors is crucial for the development of novel drugs and therapeutic protocols targeting specific receptor actions.

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References

  • Acconcia F, Kumar R (2006) Signaling regulation of genomic and nongenomic functions of estrogen receptors. Cancer Lett 238:1–14

    Article  CAS  PubMed  Google Scholar 

  • Almey A, Milner TA, Brake WG (2015) Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm Behav 74:125–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Björnström L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19(4):833–842

    Article  PubMed  Google Scholar 

  • Boonyaratanakornkit V (2011) Scaffolding proteins mediating membrane-initiated extra-nuclear actions of estrogen receptor. Steroids 76:877–884

    CAS  PubMed  Google Scholar 

  • Boonyaratanakornkit V, Edwards DP (2007) Receptor mechanisms mediating non-genomic actions of sex steroids. Semin Reprod Med 25:139–153

    Article  CAS  PubMed  Google Scholar 

  • Cato AC, Nestl A, Mink S (2002) Rapid actions of steroid receptors in cellular signaling pathways. Sci STKE 138:re9

    Google Scholar 

  • Cheng SB, Dong J, Pang Y, La Rocca J, Hixon M, Thomas P, Filardo EJ (2014) Anatomical localization and redistribution of G protein -coupled estrogen receptor-1 during the estrus cycle in mouse kidney and specific bindings to estrogen but not aldosterone. Mol Cell Endocrinol 382:950–959

    Article  CAS  PubMed  Google Scholar 

  • Contrò V, Basile JR, Proia P (2015) Sex steroid hormone receptors, their ligands, and nuclear and non-nuclear pathways. AIMS Mol Sci 2:294–310

    Article  Google Scholar 

  • Davis PJ, Lin HY, Mousa SA, Luidens MK, Hercbergs AA, Wehling M, Davis FB (2011) Overlapping nongenomic and genomic actions of thyroid hormone and steroids. Steroids 76(9):829–833

    CAS  PubMed  Google Scholar 

  • Echeverria PC, Picard D (2010) Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility. BBA-Mol Cell Res 1803(6):641–649

    CAS  Google Scholar 

  • Estrada M, Liberona JL, Miranda M, Jaimovich E (2000) Aldosterone- and testosterone –mediated intracellular calcium response in skeletal muscle cell cultures. Am J Physiol Endocrinol Metab 279:132–139

    Google Scholar 

  • Falkenstein E, Tillmann HC, Christ M, Feuring MM, Wehling M (2000) Multiple actions of steroid hormones – a focus on rapid, nongenomic effects. Pharmacol Rev 52:513–555

    CAS  PubMed  Google Scholar 

  • Felty Q, Roy D (2005) Estrogen, mitochondria and growth of cancer and non-cancer cells. J Carcinog 4(1):1

    Article  PubMed  PubMed Central  Google Scholar 

  • Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr (2000) Estrogen-induces activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 14:1649–1660

    Article  CAS  PubMed  Google Scholar 

  • Gururaj AE, Rayala SK, Vadlamudi RK, Kumar R (2006) Novel mechanisms of resistance to endocrine therapy: genomic and nongenomic considerations. Clin Cancer Res 12(3):1001S–1007S

    Article  CAS  PubMed  Google Scholar 

  • Hammes SR, Davis PJ (2015) Overlapping nongenomic and genomic actions of thyroid hormone and steroids. Best Pract Res Clin Endocrinol Metab 29(4):581–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haynes MP, Li L, Sinha D, Russell KS, Hisamoto K, Baron R, Collinge M, Sessa WC, Bender JR (2003) Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J Biol Chem 278(4):2118–2123

    Article  CAS  PubMed  Google Scholar 

  • Jensen EV, Jacobson HI (1962) Basic guides to the mechanism of estrogen action. Recent Prog Horm Res 18(4):387

    CAS  Google Scholar 

  • Kalita K, Lewandowski S, Skrzypczak M, Szymczak S, Tkaczyk M, Kaczmarek L (2004) In: Nowak JZ, Zawilska JB (eds) Receptory estrogenowe. Receptory i mechanizmy przekazywania sygnału. Wydawnictwo Naukowe PWN, Warszawa, pp 604–616

    Google Scholar 

  • Kampa M, Notas G, Pelekanou V, Troullinaki M, Andrianaki M, Azariadis K, Kampouri E, Lavrentaki K, Castanas E (2012) Early membrane initiated transcriptional effects of estrogens in breast cancer cells: first pharmacological evidence for a novel membrane estrogen receptor element (ERx). Steroids 77:959–967

    Article  CAS  PubMed  Google Scholar 

  • Kurokawa J, Furukawa T (2013) Non-genomic action of sex steroid hormones and cardiac repolarization. Biol Pharm Bull 36(1):8–12

    Article  CAS  PubMed  Google Scholar 

  • Lachowicz-Ochędalska (2005) Membrane receptors for estradiol – new way of biological action. Endokrynol Pol 56(3):322–326

    PubMed  Google Scholar 

  • Lee H, Bai W (2002) Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation. Mol Cell Biol 22(16):5835–5845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee-Ming K, Pfaff D (2016) Rapid estrogen actions on ion channels: a survey in search for mechanism. Steroids 111:46–53

    Article  Google Scholar 

  • Levin ER, Hammes SR (2016) Nuclear receptors outside the nucleus extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol 2016:783–797

    Article  Google Scholar 

  • Li L, Haynes MP, Bender JR (2003) Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proc Natl Acad Sci U S A 100:4807–4812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin AH, Li RW, Ho EY, Leung GP, Leung SW, Vanhoutte PM, Man RY (2013) Differential ligand binding affinities of human estrogen receptor-alpha isoforms. PLoS One 8(4):e63199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu Q, Ebling H, Mittler J, Baur WE, Karas RH (2002) MAP kinase mediates growth factor-induced nuclear translocation of estrogen receptor alpha. FEBS Lett 516(1–3):1–8

    Article  CAS  PubMed  Google Scholar 

  • Marino M, Galluzzo P, Ascenzi P (2006) Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics 7(8):497–508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Migliaccio A, Castoria G, Auricchio F (2007) Src-dependent signalling pathway regulation by sex-steroid hormones: therapeutic implications. Int J Biochem Cell Biol 39:1343–1348

    Article  CAS  PubMed  Google Scholar 

  • Mo Z, Liu M, Yang F, Luo H, Li Z, Tu G, Yang G (2013) GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer. Breast Cancer Res 15(6):R114

    Article  PubMed  PubMed Central  Google Scholar 

  • Norfleet AM, Thomas ML, Gametchu B, Watson CS (1999) Estrogen receptor-alpha detected on the plasma membrane of aldehyde-fixed GH(3)/B6/F10 rat pituitary tumor cells by enzyme-linked immunocytochemistry. Endocrinology 140:3805–3814

    Article  CAS  PubMed  Google Scholar 

  • O’Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, George SR (1998) Discovery of three novel G-protein-coupled receptor genes. Genomics 47(2):310–313

    Article  PubMed  Google Scholar 

  • Olde B, Munoz A (2009) GPR30/GPER1: searching for a role in estrogen physiology. Trens Endocrinol Metab 20:409–416

    Article  CAS  Google Scholar 

  • Ordonez-Moran P, Munoz A (2009) Nuclear receptors. Genomic and non-genomic effects converge. Cell Cycle 8(11):1675–1680

    Article  CAS  PubMed  Google Scholar 

  • Pappas TC, Gametchu B, Watson CS (1995) Membrane estrogen-receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J 9:404–410

    CAS  PubMed  Google Scholar 

  • Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Cobb MH (2001) Mitogen – activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183

    CAS  PubMed  Google Scholar 

  • Pedram A, Razandi M, Lewis M, Hammes S, Levin ER (2014) Membrane-localized estrogen receptor α is required for normal organ development and function. Dev Cell 29(4):482–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prossnitz ER, Maggiolini M (2009) Mechanisms of estrogen signaling and gene expression via GPR30. Mol Cell Endocrinol 308:32–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307:1625–1630

    Article  CAS  PubMed  Google Scholar 

  • Riggio M, Polo ML, Blaustein M, Colman-Lerner A, Lüthy I, Lanari C, Novaro V (2012) PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer. Carcinogenesis 33(3):509–518

    Article  CAS  PubMed  Google Scholar 

  • Schmidt BMW, Gerdes D, Feuring M, Falkenstein E, Christ M, Wehling M (2000) Rapid, nongenomic steroid actions: a new age? Front Neuroendocrinol 21:57–94

    Article  CAS  PubMed  Google Scholar 

  • Simoncini T, Genazzani AR (2003) Non-genomic actions of sex steroid hormones. Eur J Endocrinol 148:281–292

    Article  CAS  PubMed  Google Scholar 

  • Simoncini T, Mannella P, Fornari L, Caruso A, Varone G, Genazzani AR (2004) Genomic and non-genomic effects of estrogens on endothelial cells. Steroids 69:537–542

    Article  CAS  PubMed  Google Scholar 

  • Soltysik K, Czekaj P (2013) Membrane estrogen receptors – is it an alternative way of estrogen action? J Physiol Pharmacol 64:129–142

    CAS  PubMed  Google Scholar 

  • Świtalska M, Strządała L (2007) Niegenomowe działanie estrogenów. Postępy Hig Med Dośw 61:541–547

    Google Scholar 

  • Szego CM, Davis JS (1967) Adenosine 3′,5′-monophosphate in rat uterus – acute elevation by estrogen. Proc Natl Acad Sci U S A 58(4):1711–1718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toran-Allerand CD, Guan XP, MacLusky NJ, Horvath TL, Diano S, Singh M, Connolly ES, Nethrapalli IS, Tinnikov AA (2002) ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci 22:8391–8401

    CAS  PubMed  Google Scholar 

  • Vadlamudi RK, Manavathi B, Balasenthil S, Nair SS, Yang Z, Sahin AA, Kumar R (2005) Functional implications of altered subcellular localization of PELP1 in breast cancer cells. Cancer Res 65(17):7724–7732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J (2014) The many faces of estrogen signaling. Biochem Med 24(3):329–342

    Article  Google Scholar 

  • Watson CS, Campbell CH, Gametchu B (2002) The dynamic and elusive membrane estrogen receptor-alpha. Steroids 67:429–437

    Article  CAS  PubMed  Google Scholar 

  • Watson CS, Jeng YJ, Guptarak J (2011) Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways. J Steroid Biochem Mol Biol 127(1–2):44–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei C, Cao Y, Yang X, Zheng Z, Guan K, Wang Q, Tai Y, Zhang Y, Ma S, Cao Y, GeX XC, Li J, Yan H, Ling Y, Song T, Zhu L, Zhang B, Xu Q, Hu C, Bian XW, He X, Zhong H (2014) Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer. Proc Natl Acad Sci U S A 111(5):E601–E610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wróbel AM, Gregoraszczuk EŁ (2015) Action of methyl-, propyl- and butylparaben on GPR30 gene and protein expression, cAMP levels and activation of ERK1/2 and PI3K/Akt signaling pathways in MCF-7 breast cancer cells and MCF-10A non-transformed breast epithelial cells. Toxicol Lett 238(2):110–116

    Article  PubMed  Google Scholar 

  • Yamakawa K, Arita J (2004) Cross-talk between the estrogen receptor-, protein kinase A-, and mitogen-activated protein kinase-mediated signaling pathways in the regulation of lactotroph proliferation in primary culture. J Steroid Biochem Mol Biol 88(2):123–130

    Article  CAS  PubMed  Google Scholar 

  • Yue W, Wang JP, Conaway M, Masamura S, Li Y, Santen RJ (2002) Activation of the MAPK pathway enhances sensitivity of MCF-7 breast cancer cells to the mitogenic effect of estradiol. Endocrinology 143(9):3221–3229

    Article  CAS  PubMed  Google Scholar 

  • Zhang DP, Trudeau VL (2006) Integration of membrane and nuclear estrogen receptor signaling. Comp Biochem Physiol A Mol Integr Physiol 144(3):306–315

    Article  PubMed  Google Scholar 

  • Zielniok K, Gajewska M, Motyl T (2014) Molecular actions of 17 beta-estradiol and progesterone and their relationship with cellular signaling pathways. Postepy Hig Med Dosw 68:777–792

    Article  Google Scholar 

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Acknowledgments

This work was supported by Statutory Funds of Wroclaw Medical University No.: ST.E130.17.013.

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Authors and Affiliations

  1. Department of Medical Biochemistry, Wroclaw Medical University, Chalubinskiego 10, 50-368, Wroclaw, Poland

    Jolanta Saczko, Olga Michel, Agnieszka Chwiłkowska, Justyna Mączyńska & Julita Kulbacka

  2. Department of Toxicology, Wroclaw Medical University, Borowska 211, 50-552, Wroclaw, Poland

    Ewa Sawicka

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  1. Jolanta Saczko
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  2. Olga Michel
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Correspondence to Jolanta Saczko .

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  1. Wroclaw Medical University, Dept. of Medical Biochemistry, Wroclaw, Poland

    Julita Kulbacka

  2. Vytautas Magnus University, Bio. Res. Group/Bio Dept., Kaunas, Lithuania

    Saulius Satkauskas

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Saczko, J., Michel, O., Chwiłkowska, A., Sawicka, E., Mączyńska, J., Kulbacka, J. (2017). Estrogen Receptors in Cell Membranes: Regulation and Signaling. In: Kulbacka, J., Satkauskas, S. (eds) Transport Across Natural and Modified Biological Membranes and its Implications in Physiology and Therapy. Advances in Anatomy, Embryology and Cell Biology, vol 227. Springer, Cham. https://doi.org/10.1007/978-3-319-56895-9_6

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  • DOI: https://doi.org/10.1007/978-3-319-56895-9_6

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