membrane estrogen receptor
Membrane estrogen receptors (mERs) are a group of receptors which bind estrogen.{{cite journal | vauthors = Soltysik K, Czekaj P | title = Membrane estrogen receptors - is it an alternative way of estrogen action? | journal = Journal of Physiology and Pharmacology | volume = 64 | issue = 2 | pages = 129–142 | date = April 2013 | pmid = 23756388 }}{{cite journal | vauthors = Micevych PE, Kelly MJ | title = Membrane estrogen receptor regulation of hypothalamic function | journal = Neuroendocrinology | volume = 96 | issue = 2 | pages = 103–110 | year = 2012 | pmid = 22538318 | pmc = 3496782 | doi = 10.1159/000338400 }} 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.{{cite journal | vauthors = Micevych PE, Mermelstein PG | title = Membrane estrogen receptors acting through metabotropic glutamate receptors: an emerging mechanism of estrogen action in brain | journal = Molecular Neurobiology | volume = 38 | issue = 1 | pages = 66–77 | date = August 2008 | pmid = 18670908 | doi = 10.1007/s12035-008-8034-z | pmc = 2663000 }}{{cite journal | vauthors = Razandi M, Pedram A, Greene GL, Levin ER | title = Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells | journal = Molecular Endocrinology | volume = 13 | issue = 2 | pages = 307–319 | date = February 1999 | pmid = 9973260 | doi = 10.1210/mend.13.2.0239 | doi-access = free }}
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.{{cite journal | vauthors = Razandi M, Alton G, Pedram A, Ghonshani S, Webb P, Levin ER | title = Identification of a structural determinant necessary for the localization and function of estrogen receptor alpha at the plasma membrane | journal = Molecular and Cellular Biology | volume = 23 | issue = 5 | pages = 1633–1646 | date = March 2003 | pmid = 12588983 | pmc = 151696 | doi = 10.1128/MCB.23.5.1633-1646.2003 }}{{cite journal | vauthors = Levin ER | title = Plasma membrane estrogen receptors | journal = Trends in Endocrinology and Metabolism | volume = 20 | issue = 10 | pages = 477–482 | date = December 2009 | pmid = 19783454 | pmc = 3589572 | doi = 10.1016/j.tem.2009.06.009 }} Other putative mERs include GPER (GPR30), GPRC6A, ER-X, ERx and Gq-mER.{{cite journal | vauthors = Micevych PE, Kelly MJ | title = Membrane estrogen receptor regulation of hypothalamic function | journal = Neuroendocrinology | volume = 96 | issue = 2 | pages = 103–110 | date = 2012 | pmid = 22538318 | doi = 10.1159/000338400 | pmc = 3496782 }}{{cite journal | vauthors = Pi M, Parrill AL, Quarles LD | title = GPRC6A mediates the non-genomic effects of steroids | journal = The Journal of Biological Chemistry | volume = 285 | issue = 51 | pages = 39953–39964 | date = December 2010 | pmid = 20947496 | doi = 10.1074/jbc.M110.158063 | pmc = 3000977 | doi-access = free }}{{cite journal | vauthors = Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J | display-authors = 6 | title = Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications | journal = Physiological Reviews | volume = 97 | issue = 3 | pages = 1045–1087 | date = July 2017 | pmid = 28539435 | doi = 10.1152/physrev.00024.2016 | s2cid = 42396301 }}
Structure-function relationship
In mice and humans, ERβ localization in the plasma membrane occurs after palmitoylation on cysteine 418.{{Cite journal |last1=Ahluwalia |first1=Amrita |last2=Hoa |first2=Neil |last3=Moreira |first3=Debbie |last4=Aziz |first4=Daniel |last5=Singh |first5=Karanvir |last6=Patel |first6=Khushin N |last7=Levin |first7=Ellis R |date=2022-12-19 |title=Membrane Estrogen Receptor β Is Sufficient to Mitigate Cardiac Cell Pathology |journal=Endocrinology |language=en |volume=164 |issue=2 |doi=10.1210/endocr/bqac200 |pmid=36461668 |issn=1945-7170|doi-access=free }} Dimerization of mERs appears necessary for their function in rapid cell signaling.{{Cite journal |last1=Razandi |first1=Mahnaz |last2=Pedram |first2=Ali |last3=Merchenthaler |first3=Istvan |last4=Greene |first4=Geoffrey L. |last5=Levin |first5=Ellis R. |date=2004-12-01 |title=Plasma Membrane Estrogen Receptors Exist and Functions as Dimers |journal=Molecular Endocrinology |language=en |volume=18 |issue=12 |pages=2854–2865 |doi=10.1210/me.2004-0115 |pmid=15231873 |issn=0888-8809|doi-access=free }}
Signaling mechanisms
= G-protein coupled receptors =
Various electrophysiological studies support E2 signaling via GPCRs.{{Cite journal |last1=Lagrange |first1=Andre H. |last2=Rønnekleiv |first2=Oline K. |last3=Kelly |first3=Martin J. |date=1997-04-01 |title=Modulation of G Protein-Coupled Receptors by an Estrogen Receptor that Activates Protein Kinase A |url=http://molpharm.aspetjournals.org/lookup/doi/10.1124/mol.51.4.605 |journal=Molecular Pharmacology |language=en |volume=51 |issue=4 |pages=605–612 |doi=10.1124/mol.51.4.605 |pmid=9106625 |issn=0026-895X}}{{Cite journal |last1=Gu |first1=Qin |last2=Moss |first2=Robert L. |date=February 1998 |title=Novel mechanism for non-genomic action of 17β-oestradiol on kainate-induced currents in isolated rat CA1 hippocampal neurones |journal=The Journal of Physiology |language=en |volume=506 |issue=3 |pages=745–754 |doi=10.1111/j.1469-7793.1998.745bv.x |pmid=9503335 |pmc=2230751 |issn=0022-3751}}{{Cite journal |last1=Qiu |first1=Jian |last2=Bosch |first2=Martha A. |last3=Tobias |first3=Sandra C. |last4=Grandy |first4=David K. |last5=Scanlan |first5=Thomas S. |last6=Rønnekleiv |first6=Oline K. |last7=Kelly |first7=Martin J. |date=2003-10-22 |title=Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C |journal=The Journal of Neuroscience |language=en |volume=23 |issue=29 |pages=9529–9540 |doi=10.1523/JNEUROSCI.23-29-09529.2003 |pmid=14573532 |pmc=6740471 |issn=0270-6474}} 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.{{Cite journal |last=Coleman |first=Kevin, M. |date=2001 |title=Intracellular signaling pathways: nongenomic actions of estrogens and ligand-independent activation of estrogen receptors |journal=Frontiers in Bioscience |language=en |volume=6 |issue=1 |pages=D1379-91 |doi=10.2741/Coleman|pmid=11578956 |doi-access=free }}{{Cite journal |last1=Fu |first1=Xiao-Dong |last2=Simoncini |first2=Tommaso |date=August 2008 |title=Extra-nuclear signaling of estrogen receptors |journal=IUBMB Life |language=en |volume=60 |issue=8 |pages=502–510 |doi=10.1002/iub.80 |s2cid=5058096 |issn=1521-6543|doi-access=free |pmid=18618586 }}
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).{{Cite journal |last1=Smith |first1=A. W. |last2=Bosch |first2=M. A. |last3=Wagner |first3=E. J. |last4=Rønnekleiv |first4=O. K. |last5=Kelly |first5=M. J. |date=2013-09-01 |title=The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol |journal=American Journal of Physiology. Endocrinology and Metabolism |language=en |volume=305 |issue=5 |pages=E632–E640 |doi=10.1152/ajpendo.00281.2013 |pmid=23820624 |pmc=3761166 |issn=0193-1849}}{{Cite journal |last1=Kelly |first1=Martin J. |last2=Qiu |first2=Jian |last3=Wagner |first3=Edward J. |last4=Rønnekleiv |first4=Oline K. |date=December 2002 |title=Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS) |url=https://linkinghub.elsevier.com/retrieve/pii/S0960076002002492 |journal=The Journal of Steroid Biochemistry and Molecular Biology |language=en |volume=83 |issue=1–5 |pages=187–193 |doi=10.1016/S0960-0760(02)00249-2|pmid=12650715 |s2cid=21184175 }}{{Cite journal |last1=Kelly |first1=Martin J. |last2=Rønnekleiv |first2=Oline K. |date=September 2009 |title=Control of CNS neuronal excitability by estrogens via membrane-initiated signaling |journal=Molecular and Cellular Endocrinology |language=en |volume=308 |issue=1–2 |pages=17–25 |doi=10.1016/j.mce.2009.03.008 |pmc=2701913 |pmid=19549588}}
= mGluRs =
Localization of mERs in caveolae allows them to be held in close proximity to specific receptors such as mGluRs.{{Cite journal |last1=Meitzen |first1=John |last2=Britson |first2=Kyla A. |last3=Tuomela |first3=Krista |last4=Mermelstein |first4=Paul G. |date=February 2019 |title=The expression of select genes necessary for membrane-associated estrogen receptor signaling differ by sex in adult rat hippocampus |journal=Steroids |language=en |volume=142 |pages=21–27 |doi=10.1016/j.steroids.2017.09.012|pmid=28962849 |pmc=5874170 }} Various studies have demonstrated mER's ability to activate mGluR signaling, even in the absence of glutamate.{{Cite journal |last1=Micevych |first1=Paul E. |last2=Mermelstein |first2=Paul G. |date=August 2008 |title=Membrane Estrogen Receptors Acting Through Metabotropic Glutamate Receptors: An Emerging Mechanism of Estrogen Action in Brain |journal=Molecular Neurobiology |language=en |volume=38 |issue=1 |pages=66–77 |doi=10.1007/s12035-008-8034-z |pmid=18670908 |pmc=2663000 |issn=0893-7648}}{{Cite journal |last1=Boulware |first1=Marissa I. |last2=Weick |first2=Jason P. |last3=Becklund |first3=Bryan R. |last4=Kuo |first4=Sidney P. |last5=Groth |first5=Rachel D. |last6=Mermelstein |first6=Paul G. |date=2005-05-18 |title=Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein |journal=The Journal of Neuroscience |language=en |volume=25 |issue=20 |pages=5066–5078 |doi=10.1523/JNEUROSCI.1427-05.2005 |s2cid=16737794 |issn=0270-6474|doi-access=free |pmid=15901789 |pmc=6724851 }}{{Cite journal |last1=Huang |first1=Guang Zhe |last2=Woolley |first2=Catherine S. |date=June 2012 |title=Estradiol Acutely Suppresses Inhibition in the Hippocampus through a Sex-Specific Endocannabinoid and mGluR-Dependent Mechanism |journal=Neuron |language=en |volume=74 |issue=5 |pages=801–808 |doi=10.1016/j.neuron.2012.03.035|pmid=22681685 |pmc=3372866 }} 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.{{Cite journal |last1=Boulware |first1=Marissa I. |last2=Kordasiewicz |first2=Holly |last3=Mermelstein |first3=Paul G. |date=2007-09-12 |title=Caveolin Proteins Are Essential for Distinct Effects of Membrane Estrogen Receptors in Neurons |journal=The Journal of Neuroscience |language=en |volume=27 |issue=37 |pages=9941–9950 |doi=10.1523/JNEUROSCI.1647-07.2007 |pmid=17855608 |s2cid=17262672 |issn=0270-6474|doi-access=free |pmc=6672640 }}
Clinical significance
Membrane estrogen receptors have been implicated in reproductive, cardiovascular, neural, and immune function, including cancer, neurodegenerative disease, and cardiovascular disorders.{{Cite journal |last=Deroo |first=B. J. |date=2006-03-01 |title=Estrogen receptors and human disease |journal=Journal of Clinical Investigation |language=en |volume=116 |issue=3 |pages=561–570 |doi=10.1172/JCI27987 |pmid=16511588 |pmc=2373424 |issn=0021-9738}}{{Cite journal |last1=Arnal |first1=Jean-Francois |last2=Lenfant |first2=Françoise |last3=Metivier |first3=Raphaël |last4=Flouriot |first4=Gilles |last5=Henrion |first5=Daniel |last6=Adlanmerini |first6=Marine |last7=Fontaine |first7=Coralie |last8=Gourdy |first8=Pierre |last9=Chambon |first9=Pierre |last10=Katzenellenbogen |first10=Benita |last11=Katzenellenbogen |first11=John |date=2017-07-01 |title=Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications |url=https://www.physiology.org/doi/10.1152/physrev.00024.2016 |journal=Physiological Reviews |language=en |volume=97 |issue=3 |pages=1045–1087 |doi=10.1152/physrev.00024.2016 |pmid=28539435 |s2cid=42396301 |issn=0031-9333}}
= Cancer =
GPER1 pathways modify local inflammation and strengthen cellular immune responses in breast cancer and melanoma, making it a strong prognostic marker.{{Cite journal |last1=Arias-Pulido |first1=Hugo |last2=Royce |first2=Melanie |last3=Gong |first3=Yun |last4=Joste |first4=Nancy |last5=Lomo |first5=Lesley |last6=Lee |first6=Sang-Joon |last7=Chaher |first7=Nabila |last8=Verschraegen |first8=Claire |last9=Lara |first9=Juanita |last10=Prossnitz |first10=Eric R. |last11=Cristofanilli |first11=Massimo |date=August 2010 |title=GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer |journal=Breast Cancer Research and Treatment |language=en |volume=123 |issue=1 |pages=51–58 |doi=10.1007/s10549-009-0631-7 |pmid=19902352 |pmc=2904403 |issn=0167-6806}}{{Cite journal |last1=Natale |first1=Christopher A |last2=Li |first2=Jinyang |last3=Zhang |first3=Junqian |last4=Dahal |first4=Ankit |last5=Dentchev |first5=Tzvete |last6=Stanger |first6=Ben Z |last7=Ridky |first7=Todd W |date=2018-01-16 |title=Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade |journal=eLife |language=en |volume=7 |doi=10.7554/eLife.31770 |pmid=29336307 |issn=2050-084X |doi-access=free |pmc=5770157 }}{{Cite journal |last1=Levin |first1=Ellis R. |last2=Pietras |first2=Richard J. |date=April 2008 |title=Estrogen receptors outside the nucleus in breast cancer |url=http://link.springer.com/10.1007/s10549-007-9618-4 |journal=Breast Cancer Research and Treatment |language=en |volume=108 |issue=3 |pages=351–361 |doi=10.1007/s10549-007-9618-4 |pmid=17592774 |s2cid=11394158 |issn=0167-6806}}
= 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.{{Cite journal |last1=Roque |first1=C. |last2=Mendes-Oliveira |first2=J. |last3=Duarte-Chendo |first3=C. |last4=Baltazar |first4=G. |date=October 2019 |title=The role of G protein-coupled estrogen receptor 1 on neurological disorders |url=https://linkinghub.elsevier.com/retrieve/pii/S0091302219300482 |journal=Frontiers in Neuroendocrinology |language=en |volume=55 |pages=100786 |doi=10.1016/j.yfrne.2019.100786|pmid=31513775 |s2cid=202043731 }}{{Cite journal |last1=Cerri |first1=Silvia |last2=Mus |first2=Liudmila |last3=Blandini |first3=Fabio |date=2019-07-30 |title=Parkinson's Disease in Women and Men: What's the Difference? |journal=Journal of Parkinson's Disease |volume=9 |issue=3 |pages=501–515 |doi=10.3233/JPD-191683|pmid=31282427 |pmc=6700650 }}
= Cardiovascular disorders =
mERβ has been demonstrated to mitigate cardiac cell pathology caused by angiotensin II.{{Cite journal |last1=Qian |first1=Chenyue |last2=Liu |first2=Jingjin |last3=Liu |first3=Huadong |date=2023-10-03 |title=Targeting estrogen receptor signaling for treating heart failure |journal=Heart Failure Reviews |volume=29 |issue=1 |pages=125–131 |language=en |doi=10.1007/s10741-023-10356-9 |s2cid=263607262 |issn=1573-7322|doi-access=free |pmid=37783987 |pmc=10904494 }} 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.{{Cite journal |last1=Mendelsohn |first1=Michael E. |last2=Karas |first2=Richard H. |date=2010-07-01 |title=Rapid progress for non-nuclear estrogen receptor signaling |url=http://www.jci.org/articles/view/43756 |journal=Journal of Clinical Investigation |language=en |volume=120 |issue=7 |pages=2277–2279 |doi=10.1172/JCI43756 |pmid=20577045 |pmc=2898619 |issn=0021-9738}}
= Addiction =
Propensity to addiction appears to be mediated by sex hormones such as estrogen.{{Cite journal |last1=Fattore |first1=Liana |last2=Melis |first2=Miriam |last3=Fadda |first3=Paola |last4=Fratta |first4=Walter |date=August 2014 |title=Sex differences in addictive disorders |url=https://linkinghub.elsevier.com/retrieve/pii/S0091302214000454 |journal=Frontiers in Neuroendocrinology |language=en |volume=35 |issue=3 |pages=272–284 |doi=10.1016/j.yfrne.2014.04.003|pmid=24769267 |s2cid=45385549 }} 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.{{Cite journal |last1=Martinez |first1=Luis A. |last2=Peterson |first2=Brittni M. |last3=Meisel |first3=Robert L. |last4=Mermelstein |first4=Paul G. |date=September 2014 |title=Estradiol facilitation of cocaine-induced locomotor sensitization in female rats requires activation of mGluR5 |journal=Behavioural Brain Research |language=en |volume=271 |pages=39–42 |doi=10.1016/j.bbr.2014.05.052|pmid=24893316 |pmc=4636080 }}{{Cite journal |last1=Tonn Eisinger |first1=Katherine R. |last2=Larson |first2=Erin B. |last3=Boulware |first3=Marissa I. |last4=Thomas |first4=Mark J. |last5=Mermelstein |first5=Paul G. |date=May 2018 |title=Membrane estrogen receptor signaling impacts the reward circuitry of the female brain to influence motivated behaviors |journal=Steroids |language=en |volume=133 |pages=53–59 |doi=10.1016/j.steroids.2017.11.013|pmid=29195840 |pmc=5864533 }}