Wikipedia

Membrane estrogen receptor

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

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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

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G-protein coupled receptors

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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

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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

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

Cancer

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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

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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

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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

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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

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References

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  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. ^ a b 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. ^ a b 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.
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  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.
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  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.
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  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.
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