Membrane estrogen receptor

Last updated

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]

Contents

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]

ERa/ERb becoming mERs through trafficking to the membrane by caveolins, following palmitoylation. MER localization.pdf
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. ↑ Soltysik K, Czekaj P (April 2013). "Membrane estrogen receptors - is it an alternative way of estrogen action?". Journal of Physiology and Pharmacology. 64 (2): 129–142. PMID   23756388.
  2. ↑ Micevych PE, Kelly MJ (2012). "Membrane estrogen receptor regulation of hypothalamic function". Neuroendocrinology. 96 (2): 103–110. doi:10.1159/000338400. PMC   3496782 . PMID   22538318.
  3. 1 2 Micevych PE, Mermelstein PG (August 2008). "Membrane estrogen receptors acting through metabotropic glutamate receptors: an emerging mechanism of estrogen action in brain". Molecular Neurobiology. 38 (1): 66–77. doi:10.1007/s12035-008-8034-z. PMC   2663000 . PMID   18670908.
  4. ↑ Razandi M, Pedram A, Greene GL, Levin ER (February 1999). "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. doi: 10.1210/mend.13.2.0239 . PMID   9973260.
  5. ↑ Razandi M, Alton G, Pedram A, Ghonshani S, Webb P, Levin ER (March 2003). "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. doi:10.1128/MCB.23.5.1633-1646.2003. PMC   151696 . PMID   12588983.
  6. ↑ Levin ER (December 2009). "Plasma membrane estrogen receptors". Trends in Endocrinology and Metabolism. 20 (10): 477–482. doi:10.1016/j.tem.2009.06.009. PMC   3589572 . PMID   19783454.
  7. ↑ Micevych PE, Kelly MJ (2012). "Membrane estrogen receptor regulation of hypothalamic function". Neuroendocrinology. 96 (2): 103–110. doi:10.1159/000338400. PMC   3496782 . PMID   22538318.
  8. ↑ Pi M, Parrill AL, Quarles LD (December 2010). "GPRC6A mediates the non-genomic effects of steroids". The Journal of Biological Chemistry. 285 (51): 39953–39964. doi: 10.1074/jbc.M110.158063 . PMC   3000977 . PMID   20947496.
  9. ↑ Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, et al. (July 2017). "Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications". Physiological Reviews. 97 (3): 1045–1087. doi:10.1152/physrev.00024.2016. PMID   28539435. S2CID   42396301.
  10. 1 2 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". Endocrinology. 164 (2). doi: 10.1210/endocr/bqac200 . ISSN   1945-7170. PMID   36461668.
  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". Molecular Endocrinology. 18 (12): 2854–2865. doi: 10.1210/me.2004-0115 . ISSN   0888-8809. PMID   15231873.
  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" . Molecular Pharmacology. 51 (4): 605–612. doi:10.1124/mol.51.4.605. ISSN   0026-895X. PMID   9106625.
  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". The Journal of Physiology. 506 (3): 745–754. doi:10.1111/j.1469-7793.1998.745bv.x. ISSN   0022-3751. PMC   2230751 . 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". The Journal of Neuroscience. 23 (29): 9529–9540. doi:10.1523/JNEUROSCI.23-29-09529.2003. ISSN   0270-6474. PMC   6740471 . PMID   14573532.
  15. ↑ Coleman, Kevin, M. (2001). "Intracellular signaling pathways: nongenomic actions of estrogens and ligand-independent activation of estrogen receptors". Frontiers in Bioscience. 6 (1): D1379-91. doi: 10.2741/Coleman . PMID   11578956.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ↑ Fu, Xiao-Dong; Simoncini, Tommaso (August 2008). "Extra-nuclear signaling of estrogen receptors". IUBMB Life. 60 (8): 502–510. doi: 10.1002/iub.80 . ISSN   1521-6543. PMID   18618586. S2CID   5058096.
  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". American Journal of Physiology. Endocrinology and Metabolism. 305 (5): E632 –E640. doi:10.1152/ajpendo.00281.2013. ISSN   0193-1849. PMC   3761166 . 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)" . The Journal of Steroid Biochemistry and Molecular Biology. 83 (1–5): 187–193. doi:10.1016/S0960-0760(02)00249-2. PMID   12650715. S2CID   21184175.
  19. ↑ Kelly, Martin J.; Rønnekleiv, Oline K. (September 2009). "Control of CNS neuronal excitability by estrogens via membrane-initiated signaling". Molecular and Cellular Endocrinology. 308 (1–2): 17–25. doi:10.1016/j.mce.2009.03.008. PMC   2701913 . 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". Steroids. 142: 21–27. doi:10.1016/j.steroids.2017.09.012. PMC   5874170 . 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". Molecular Neurobiology. 38 (1): 66–77. doi:10.1007/s12035-008-8034-z. ISSN   0893-7648. PMC   2663000 . 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". The Journal of Neuroscience. 25 (20): 5066–5078. doi: 10.1523/JNEUROSCI.1427-05.2005 . ISSN   0270-6474. PMC   6724851 . PMID   15901789. S2CID   16737794.
  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". Neuron. 74 (5): 801–808. doi:10.1016/j.neuron.2012.03.035. PMC   3372866 . 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". The Journal of Neuroscience. 27 (37): 9941–9950. doi: 10.1523/JNEUROSCI.1647-07.2007 . ISSN   0270-6474. PMC   6672640 . PMID   17855608. S2CID   17262672.
  25. ↑ Deroo, B. J. (2006-03-01). "Estrogen receptors and human disease". Journal of Clinical Investigation. 116 (3): 561–570. doi:10.1172/JCI27987. ISSN   0021-9738. PMC   2373424 . PMID   16511588.
  26. ↑ Arnal, Jean-Francois; Lenfant, Françoise; Metivier, Raphaël; Flouriot, Gilles; Henrion, Daniel; Adlanmerini, Marine; Fontaine, Coralie; Gourdy, Pierre; Chambon, Pierre; Katzenellenbogen, Benita; Katzenellenbogen, John (2017-07-01). "Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications" . Physiological Reviews. 97 (3): 1045–1087. doi:10.1152/physrev.00024.2016. ISSN   0031-9333. PMID   28539435. S2CID   42396301.
  27. ↑ Arias-Pulido, Hugo; Royce, Melanie; Gong, Yun; Joste, Nancy; Lomo, Lesley; Lee, Sang-Joon; Chaher, Nabila; Verschraegen, Claire; Lara, Juanita; Prossnitz, Eric R.; Cristofanilli, Massimo (August 2010). "GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer". Breast Cancer Research and Treatment. 123 (1): 51–58. doi:10.1007/s10549-009-0631-7. ISSN   0167-6806. PMC   2904403 . 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". eLife. 7. doi: 10.7554/eLife.31770 . ISSN   2050-084X. PMC   5770157 . PMID   29336307.
  29. ↑ Levin, Ellis R.; Pietras, Richard J. (April 2008). "Estrogen receptors outside the nucleus in breast cancer" . Breast Cancer Research and Treatment. 108 (3): 351–361. doi:10.1007/s10549-007-9618-4. ISSN   0167-6806. PMID   17592774. S2CID   11394158.
  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" . Frontiers in Neuroendocrinology. 55: 100786. doi:10.1016/j.yfrne.2019.100786. PMID   31513775. S2CID   202043731.
  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. PMC   6700650 . PMID   31282427.
  32. ↑ Qian, Chenyue; Liu, Jingjin; Liu, Huadong (2023-10-03). "Targeting estrogen receptor signaling for treating heart failure". Heart Failure Reviews. 29 (1): 125–131. doi: 10.1007/s10741-023-10356-9 . ISSN   1573-7322. PMC   10904494 . PMID   37783987. S2CID   263607262.
  33. ↑ Mendelsohn, Michael E.; Karas, Richard H. (2010-07-01). "Rapid progress for non-nuclear estrogen receptor signaling". Journal of Clinical Investigation. 120 (7): 2277–2279. doi:10.1172/JCI43756. ISSN   0021-9738. PMC   2898619 . PMID   20577045.
  34. ↑ Fattore, Liana; Melis, Miriam; Fadda, Paola; Fratta, Walter (August 2014). "Sex differences in addictive disorders" . Frontiers in Neuroendocrinology. 35 (3): 272–284. doi:10.1016/j.yfrne.2014.04.003. PMID   24769267. S2CID   45385549.
  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". Behavioural Brain Research. 271: 39–42. doi:10.1016/j.bbr.2014.05.052. PMC   4636080 . 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". Steroids. 133: 53–59. doi:10.1016/j.steroids.2017.11.013. PMC   5864533 . PMID   29195840.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.