Biology:Membrane estrogen receptor

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Membrane estrogen receptors (mERs) are a group of receptors which bind estrogen.[1][2] Unlike nuclear estrogen receptors, which mediate their effects via slower genomic mechanisms, mERs are cell surface receptors that rapidly alter cell signaling via modulation of intracellular signaling cascades.[3][4] Nuclear estrogen receptors such as ERα and ERβ become mERs through palmitoylation, a post-translational modification that enhances ER association with caveolin-1 to enable trafficking of ERs to the membrane or membrane caveolae.[5][6] Other putative mERs include GPER (GPR30), GPRC6A, ER-X, ERx and Gq-mER.[3][7][8][9]

membrane ER localization by caveolins following palmitoylation.
ERα/ERβ becoming mERs through trafficking to the membrane by caveolins, following palmitoylation.

Structure-function relationship

In mice and humans, ERβ localization in the plasma membrane occurs after palmitoylation on cysteine 418.[10] Dimerization of mERs appears necessary for their function in rapid cell signaling.[11]

Signaling mechanisms

G-protein coupled receptors

Various electrophysiological studies support E2 signaling via GPCRs.[12][13][14] mERs are thought to activate G-protein coupled receptors to regulate L-type Ca2+ channels and activate protein kinase A (PKA), protein kinase C (PKC), and mitogen activated protein kinase (MAPK) signaling cascades.[15][16]

Gq-coupled mERs (Gq-mERs) activation has been demonstrated to rapidly increase membrane excitability various neuronal cell types by desensitizing GABAB receptor coupling to G protein-coupled inwardly rectifying K+ channels (GIRKs).[17][18][19]

mGluRs

Localization of mERs in caveolae allows them to be held in close proximity to specific receptors such as mGluRs.[20] Various studies have demonstrated mER's ability to activate mGluR signaling, even in the absence of glutamate.[21][22][23] ER/mGluR signaling is thought to be highly relevant for female motivational behavior. Interestingly, modification of caveolin expression appears to alter the nature of ER-mGluR interactions.[24]

Clinical significance

Membrane estrogen receptors have been implicated in reproductive, cardiovascular, neural, and immune function, including cancer, neurodegenerative disease, and cardiovascular disorders.[25][26]

Cancer

GPER1 pathways modify local inflammation and strengthen cellular immune responses in breast cancer and melanoma, making it a strong prognostic marker.[27][28][29]

Neurodegenerative disease

mERs have a demonstrated neuroprotective effect against neurodegenerative disorders like Parkinson's disease, which is thought to underlie the lower incidence of the disorder in women compared to men.[30][31]

Cardiovascular disorders

mERβ has been demonstrated to mitigate cardiac cell pathology caused by angiotensin II.[10][32] Activation of mER but not nuclear ER signaling in vascular epithelial cells promotes protection against vascular injury in mice. Striatin, a scaffolding protein that links mERs to membrane caveolae, is necessary for this effect.[33]

Addiction

Propensity to addiction appears to be mediated by sex hormones such as estrogen.[34] In neural reward circuity, nuclear ERs are not commonly expressed, and mERs have been demonstrated to act on mGluR5 to facilitate psychostimulant-induced behavioral and neurochemical effects.[35][36]

See also

References

  1. ↑ "Membrane estrogen receptors - is it an alternative way of estrogen action?". Journal of Physiology and Pharmacology 64 (2): 129–142. April 2013. PMID 23756388. 
  2. ↑ "Membrane estrogen receptor regulation of hypothalamic function". Neuroendocrinology 96 (2): 103–110. 2012. doi:10.1159/000338400. PMID 22538318. 
  3. ↑ 3.0 3.1 "Membrane estrogen receptors acting through metabotropic glutamate receptors: an emerging mechanism of estrogen action in brain". Molecular Neurobiology 38 (1): 66–77. August 2008. doi:10.1007/s12035-008-8034-z. PMID 18670908. 
  4. ↑ "Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells". Molecular Endocrinology 13 (2): 307–319. February 1999. doi:10.1210/mend.13.2.0239. PMID 9973260. 
  5. ↑ "Identification of a structural determinant necessary for the localization and function of estrogen receptor alpha at the plasma membrane". Molecular and Cellular Biology 23 (5): 1633–1646. March 2003. doi:10.1128/MCB.23.5.1633-1646.2003. PMID 12588983. 
  6. ↑ "Plasma membrane estrogen receptors". Trends in Endocrinology and Metabolism 20 (10): 477–482. December 2009. doi:10.1016/j.tem.2009.06.009. PMID 19783454. 
  7. ↑ "Membrane estrogen receptor regulation of hypothalamic function". Neuroendocrinology 96 (2): 103–110. 2012. doi:10.1159/000338400. PMID 22538318. 
  8. ↑ "GPRC6A mediates the non-genomic effects of steroids". The Journal of Biological Chemistry 285 (51): 39953–39964. December 2010. doi:10.1074/jbc.M110.158063. PMID 20947496. 
  9. ↑ "Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications". Physiological Reviews 97 (3): 1045–1087. July 2017. doi:10.1152/physrev.00024.2016. PMID 28539435. 
  10. ↑ 10.0 10.1 Ahluwalia, Amrita; Hoa, Neil; Moreira, Debbie; Aziz, Daniel; Singh, Karanvir; Patel, Khushin N; Levin, Ellis R (2022-12-19). "Membrane Estrogen Receptor β Is Sufficient to Mitigate Cardiac Cell Pathology" (in en). Endocrinology 164 (2). doi:10.1210/endocr/bqac200. ISSN 1945-7170. PMID 36461668. https://academic.oup.com/endo/article/doi/10.1210/endocr/bqac200/6867852. 
  11. ↑ Razandi, Mahnaz; Pedram, Ali; Merchenthaler, Istvan; Greene, Geoffrey L.; Levin, Ellis R. (2004-12-01). "Plasma Membrane Estrogen Receptors Exist and Functions as Dimers" (in en). Molecular Endocrinology 18 (12): 2854–2865. doi:10.1210/me.2004-0115. ISSN 0888-8809. PMID 15231873. https://academic.oup.com/mend/article/18/12/2854/2741688. 
  12. ↑ Lagrange, Andre H.; Rønnekleiv, Oline K.; Kelly, Martin J. (1997-04-01). "Modulation of G Protein-Coupled Receptors by an Estrogen Receptor that Activates Protein Kinase A" (in en). Molecular Pharmacology 51 (4): 605–612. doi:10.1124/mol.51.4.605. ISSN 0026-895X. PMID 9106625. http://molpharm.aspetjournals.org/lookup/doi/10.1124/mol.51.4.605. 
  13. ↑ Gu, Qin; Moss, Robert L. (February 1998). "Novel mechanism for non‐genomic action of 17β‐oestradiol on kainate‐induced currents in isolated rat CA1 hippocampal neurones" (in en). The Journal of Physiology 506 (3): 745–754. doi:10.1111/j.1469-7793.1998.745bv.x. ISSN 0022-3751. PMID 9503335. 
  14. ↑ Qiu, Jian; Bosch, Martha A.; Tobias, Sandra C.; Grandy, David K.; Scanlan, Thomas S.; Rønnekleiv, Oline K.; Kelly, Martin J. (2003-10-22). "Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C" (in en). The Journal of Neuroscience 23 (29): 9529–9540. doi:10.1523/JNEUROSCI.23-29-09529.2003. ISSN 0270-6474. PMID 14573532. 
  15. ↑ Coleman, Kevin, M. (2001). "Intracellular signaling pathways: nongenomic actions of estrogens and ligand-independent activation of estrogen receptors" (in en). Frontiers in Bioscience 6 (1): D1379-91. doi:10.2741/Coleman. PMID 11578956. https://imrpress.com/journal/FBL/6/3/10.2741/coleman. 
  16. ↑ Fu, Xiao‐Dong; Simoncini, Tommaso (August 2008). "Extra‐nuclear signaling of estrogen receptors" (in en). IUBMB Life 60 (8): 502–510. doi:10.1002/iub.80. ISSN 1521-6543. https://iubmb.onlinelibrary.wiley.com/doi/10.1002/iub.80. 
  17. ↑ Smith, A. W.; Bosch, M. A.; Wagner, E. J.; Rønnekleiv, O. K.; Kelly, M. J. (2013-09-01). "The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol" (in en). American Journal of Physiology-Endocrinology and Metabolism 305 (5): E632–E640. doi:10.1152/ajpendo.00281.2013. ISSN 0193-1849. PMID 23820624. 
  18. ↑ Kelly, Martin J.; Qiu, Jian; Wagner, Edward J.; Rønnekleiv, Oline K. (December 2002). "Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS)" (in en). The Journal of Steroid Biochemistry and Molecular Biology 83 (1–5): 187–193. doi:10.1016/S0960-0760(02)00249-2. PMID 12650715. https://linkinghub.elsevier.com/retrieve/pii/S0960076002002492. 
  19. ↑ Kelly, Martin J.; Rønnekleiv, Oline K. (September 2009). "Control of CNS neuronal excitability by estrogens via membrane-initiated signaling" (in en). Molecular and Cellular Endocrinology 308 (1–2): 17–25. doi:10.1016/j.mce.2009.03.008. PMID 19549588. 
  20. ↑ Meitzen, John; Britson, Kyla A.; Tuomela, Krista; Mermelstein, Paul G. (February 2019). "The expression of select genes necessary for membrane-associated estrogen receptor signaling differ by sex in adult rat hippocampus" (in en). Steroids 142: 21–27. doi:10.1016/j.steroids.2017.09.012. PMID 28962849. 
  21. ↑ Micevych, Paul E.; Mermelstein, Paul G. (August 2008). "Membrane Estrogen Receptors Acting Through Metabotropic Glutamate Receptors: An Emerging Mechanism of Estrogen Action in Brain" (in en). Molecular Neurobiology 38 (1): 66–77. doi:10.1007/s12035-008-8034-z. ISSN 0893-7648. PMID 18670908. 
  22. ↑ Boulware, Marissa I.; Weick, Jason P.; Becklund, Bryan R.; Kuo, Sidney P.; Groth, Rachel D.; Mermelstein, Paul G. (2005-05-18). "Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein" (in en). The Journal of Neuroscience 25 (20): 5066–5078. doi:10.1523/JNEUROSCI.1427-05.2005. ISSN 0270-6474. PMC 6724851. https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.1427-05.2005. 
  23. ↑ Huang, Guang Zhe; Woolley, Catherine S. (June 2012). "Estradiol Acutely Suppresses Inhibition in the Hippocampus through a Sex-Specific Endocannabinoid and mGluR-Dependent Mechanism" (in en). Neuron 74 (5): 801–808. doi:10.1016/j.neuron.2012.03.035. PMID 22681685. 
  24. ↑ Boulware, Marissa I.; Kordasiewicz, Holly; Mermelstein, Paul G. (2007-09-12). "Caveolin Proteins Are Essential for Distinct Effects of Membrane Estrogen Receptors in Neurons" (in en). The Journal of Neuroscience 27 (37): 9941–9950. doi:10.1523/JNEUROSCI.1647-07.2007. ISSN 0270-6474. PMID 17855608. PMC 6672640. https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.1647-07.2007. 
  25. ↑ Deroo, B. J. (2006-03-01). "Estrogen receptors and human disease" (in en). Journal of Clinical Investigation 116 (3): 561–570. doi:10.1172/JCI27987. ISSN 0021-9738. PMID 16511588. 
  26. ↑ Arnal, Jean-Francois; Lenfant, Françoise; Metivier, Raphaël; Flouriot, Gilles; Henrion, Daniel; Adlanmerini, Marine; Fontaine, Coralie; Gourdy, Pierre et al. (2017-07-01). "Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications" (in en). Physiological Reviews 97 (3): 1045–1087. doi:10.1152/physrev.00024.2016. ISSN 0031-9333. PMID 28539435. https://www.physiology.org/doi/10.1152/physrev.00024.2016. 
  27. ↑ Arias-Pulido, Hugo; Royce, Melanie; Gong, Yun; Joste, Nancy; Lomo, Lesley; Lee, Sang-Joon; Chaher, Nabila; Verschraegen, Claire et al. (August 2010). "GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer" (in en). Breast Cancer Research and Treatment 123 (1): 51–58. doi:10.1007/s10549-009-0631-7. ISSN 0167-6806. PMID 19902352. 
  28. ↑ Natale, Christopher A; Li, Jinyang; Zhang, Junqian; Dahal, Ankit; Dentchev, Tzvete; Stanger, Ben Z; Ridky, Todd W (2018-01-16). "Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade" (in en). eLife 7. doi:10.7554/eLife.31770. ISSN 2050-084X. PMID 29336307. PMC 5770157. https://elifesciences.org/articles/31770. 
  29. ↑ Levin, Ellis R.; Pietras, Richard J. (April 2008). "Estrogen receptors outside the nucleus in breast cancer" (in en). Breast Cancer Research and Treatment 108 (3): 351–361. doi:10.1007/s10549-007-9618-4. ISSN 0167-6806. PMID 17592774. http://link.springer.com/10.1007/s10549-007-9618-4. 
  30. ↑ Roque, C.; Mendes-Oliveira, J.; Duarte-Chendo, C.; Baltazar, G. (October 2019). "The role of G protein-coupled estrogen receptor 1 on neurological disorders" (in en). Frontiers in Neuroendocrinology 55: 100786. doi:10.1016/j.yfrne.2019.100786. PMID 31513775. https://linkinghub.elsevier.com/retrieve/pii/S0091302219300482. 
  31. ↑ Cerri, Silvia; Mus, Liudmila; Blandini, Fabio (2019-07-30). "Parkinson's Disease in Women and Men: What's the Difference?". Journal of Parkinson's Disease 9 (3): 501–515. doi:10.3233/JPD-191683. PMID 31282427. 
  32. ↑ Qian, Chenyue; Liu, Jingjin; Liu, Huadong (2023-10-03). "Targeting estrogen receptor signaling for treating heart failure" (in en). Heart Failure Reviews. doi:10.1007/s10741-023-10356-9. ISSN 1573-7322. https://link.springer.com/10.1007/s10741-023-10356-9. 
  33. ↑ Mendelsohn, Michael E.; Karas, Richard H. (2010-07-01). "Rapid progress for non-nuclear estrogen receptor signaling" (in en). Journal of Clinical Investigation 120 (7): 2277–2279. doi:10.1172/JCI43756. ISSN 0021-9738. PMID 20577045. PMC 2898619. http://www.jci.org/articles/view/43756. 
  34. ↑ Fattore, Liana; Melis, Miriam; Fadda, Paola; Fratta, Walter (August 2014). "Sex differences in addictive disorders" (in en). Frontiers in Neuroendocrinology 35 (3): 272–284. doi:10.1016/j.yfrne.2014.04.003. PMID 24769267. https://linkinghub.elsevier.com/retrieve/pii/S0091302214000454. 
  35. ↑ Martinez, Luis A.; Peterson, Brittni M.; Meisel, Robert L.; Mermelstein, Paul G. (September 2014). "Estradiol facilitation of cocaine-induced locomotor sensitization in female rats requires activation of mGluR5" (in en). Behavioural Brain Research 271: 39–42. doi:10.1016/j.bbr.2014.05.052. PMID 24893316. 
  36. ↑ Tonn Eisinger, Katherine R.; Larson, Erin B.; Boulware, Marissa I.; Thomas, Mark J.; Mermelstein, Paul G. (May 2018). "Membrane estrogen receptor signaling impacts the reward circuitry of the female brain to influence motivated behaviors" (in en). Steroids 133: 53–59. doi:10.1016/j.steroids.2017.11.013. PMID 29195840. 



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