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Pang, Y. & Thomas, P. Additive effects of low concentrations of estradiol-17β and progesterone on nitric oxide production by human vascular endothelial cells through shared signaling pathways. J. Steroid Biochem. Mol. Biol. 165, 258–267 (2017).

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Yu, X., Stallone, J. N., Heaps, C. L. & Han, G. The activation of G protein-coupled estrogen receptor induces relaxation via cAMP as well as potentiates contraction via EGFR transactivation in porcine coronary arteries. PLoS ONE 13, e0191418 (2018).

pubmed: 29360846 doi: 10.1371/journal.pone.0191418 pmcid: 5779678

Yu, X. et al. Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA. PLoS ONE 12, e0173085 (2017).

pubmed: 28278256 doi: 10.1371/journal.pone.0173085 pmcid: 5344336

Meyer, M. R., Fredette, N. C., Barton, M. & Prossnitz, E. R. G protein-coupled estrogen receptor inhibits vascular prostanoid production and activity. J. Endocrinol. 227, 61–69 (2015).

pubmed: 26303299 doi: 10.1530/JOE-15-0257 pmcid: 4782600

Meyer, M. R., Field, A. S., Kanagy, N. L., Barton, M. & Prossnitz, E. R. GPER regulates endothelin-dependent vascular tone and intracellular calcium. Life Sci. 91, 623–627 (2012).

pubmed: 22326502 doi: 10.1016/j.lfs.2012.01.007 pmcid: 3355219

Tropea, T. et al. Pregnancy augments G protein estrogen receptor (GPER) induced vasodilation in rat uterine arteries via the nitric oxide–cGMP signaling pathway. PLoS ONE 10, e0141997 (2015).

pubmed: 26536245 doi: 10.1371/journal.pone.0141997 pmcid: 4633123

Gurrala, R. et al. Alterations in the estrogen receptor profile of cardiovascular tissues during aging. Geroscience 43, 433–442 (2021).

pubmed: 33558965 doi: 10.1007/s11357-021-00331-3 pmcid: 8050209

Meyer, M. R., Rosemann, T., Barton, M. & Prossnitz, E. R. GPER mediates functional endothelial aging in renal arteries. Pharmacology 100, 188–193 (2017).

pubmed: 28704834 doi: 10.1159/000478732

Davis, G. K., Newsome, A. D., Cole, A. B., Ojeda, N. B. & Alexander, B. T. Chronic estrogen supplementation prevents the increase in blood pressure in female intrauterine growth-restricted offspring at 12 months of age. Hypertension 73, 1128–1136 (2019).

pubmed: 30929518 doi: 10.1161/HYPERTENSIONAHA.118.12379

Luo, P. et al. Stress-related arterial hypertension in Gper-deficient rats. Acta Physiol. Sin. 69, 532–540 (2017).

Waghulde, H. et al. Attenuation of microbiotal dysbiosis and hypertension in a CRISPR/Cas9 gene ablation rat model of GPER1. Hypertension 72, 1125–1132 (2018).

pubmed: 30354811 doi: 10.1161/HYPERTENSIONAHA.118.11175

Gohar, E. Y. et al. Evidence for G-protein-coupled estrogen receptor as a pronatriuretic factor. J. Am. Heart Assoc. 9, e015110 (2020). This study reports the identification of GPER as a modulator of natriuresis.

pubmed: 32390531 doi: 10.1161/JAHA.119.015110 pmcid: 7660860

Barton, M. & Meyer, M. R. Nicolaus Copernicus and the rapid vascular responses to aldosterone. Trends Endocrinol. Metab. 26, 396–398 (2015).

pubmed: 26088671 doi: 10.1016/j.tem.2015.05.005

Wehling, M. Rapid actions of aldosterone revisited: receptors in the limelight. J. Steroid Biochem. Mol. Biol. 176, 94–98 (2018).

pubmed: 28126566 doi: 10.1016/j.jsbmb.2017.01.016

Dinh, Q. N. et al. Aldosterone-induced hypertension is sex-dependent, mediated by T cells and sensitive to GPER activation. Cardiovasc. Res. 117, 960–970 (2021). An important study identifying T cell-mediated mechanisms involving GPER as sex-dependent modifiers of aldosterone-dependent arterial hypertension.

pubmed: 32215568 doi: 10.1093/cvr/cvaa075

Caroccia, B. et al. Aldosterone stimulates its biosynthesis via a novel GPER-mediated mechanism. J. Clin. Endocrinol. Metab. 104, 6316–6324 (2019). This study reports the regulation of adrenal aldosterone biosynthesis involving GPER-dependent mechanisms.

pubmed: 31125081 doi: 10.1210/jc.2019-00043

Wang, D., Wang, M., Sun, P. & Gao, Q. Eplerenone inhibits oxidized low-density lipoprotein-induced proliferation and migration of vascular smooth muscle cells by downregulating GPER expression. Adv. Clin. Exp. Med. 30, 405–412 (2021).

pubmed: 33915037 doi: 10.17219/acem/133484

Cheng, L. et al. Rapid aldosterone-mediated signaling in the DCT increases activity of the thiazide-sensitive NaCl cotransporter. J. Am. Soc. Nephrol. 30, 1454–1470 (2019).

pubmed: 31253651 doi: 10.1681/ASN.2018101025 pmcid: 6683706

Sharma, G. et al. GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state. Endocrinology 154, 4136–4145 (2013).

pubmed: 23970785 doi: 10.1210/en.2013-1357 pmcid: 3800768

Meoli, L. et al. Sex- and age-dependent effects of Gpr30 genetic deletion on the metabolic and cardiovascular profiles of diet-induced obese mice. Gene 540, 210–216 (2014).

pubmed: 24582972 doi: 10.1016/j.gene.2014.02.036

Ghaffari, S., Naderi Nabi, F., Sugiyama, M. G. & Lee, W. L. Estrogen inhibits LDL (low-density lipoprotein) transcytosis by human coronary artery endothelial cells via GPER (G-protein-coupled estrogen receptor) and SR-BI (scavenger receptor class B type 1). Arterioscler. Thromb. Vasc. Biol. 38, 2283–2294 (2018). This study demonstrated that oestrogen-dependent inhibition of LDL cholesterol transcytosis, which is involved in early atherogenesis, is mediated by GPER and scavenger receptor B1.

pubmed: 30354216 doi: 10.1161/ATVBAHA.118.310792

Jafarynezhad, F. et al. The G-protein-coupled estrogen receptor agonist prevents cardiac lipid accumulation by stimulating cardiac peroxisome proliferator-activated receptor alpha: a preclinical study in ovariectomized-diabetic rat model. Int. J. Endocrinol. Metab. 20, e123560 (2022).

pubmed: 36407026 doi: 10.5812/ijem-123560 pmcid: 9661540

Locher, R., Emmanuele, L., Suter, P. M., Vetter, W. & Barton, M. Green tea polyphenols inhibit human vascular smooth muscle cell proliferation stimulated by native low-density lipoprotein. Eur. J. Pharmacol. 434, 1–7 (2002).

pubmed: 11755158 doi: 10.1016/S0014-2999(01)01535-7

Blasko, E. et al. Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis. J. Neuroimmunol. 214, 67–77 (2009). One of two studies to first suggest a role for GPER in experimental multiple sclerosis.

pubmed: 19664827 doi: 10.1016/j.jneuroim.2009.06.023 pmcid: 2873862

Pelekanou, V. et al. Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1. J. Leukoc. Biol. 99, 333–347 (2016).

pubmed: 26394816 doi: 10.1189/jlb.3A0914-430RR

Haas, E. et al. Differential effects of 17β-estradiol on function and expression of estrogen receptor alpha, estrogen receptor beta, and GPR30 in arteries and veins of patients with atherosclerosis. Hypertension 49, 1358–1363 (2007).

pubmed: 17452498 doi: 10.1161/HYPERTENSIONAHA.107.089995

Li, F. et al. Activation of GPER induces differentiation and inhibition of coronary artery smooth muscle cell proliferation. PLoS ONE 8, e64771 (2013).

pubmed: 23840305 doi: 10.1371/journal.pone.0064771 pmcid: 3686788

Jehle, J. et al. G protein-coupled estrogen receptor GPR30 exerts vasoprotective effects in apolipoprotein E-deficient mice. Arch. Med. Sci. https://doi.org/10.5114/aoms/127200 (2021).

doi: 10.5114/aoms/127200

Moreno-Ulloa, A. et al. The effects of (-)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER). Pharmacol. Res. 100, 309–320 (2015).

pubmed: 26303816 doi: 10.1016/j.phrs.2015.08.014 pmcid: 4555879

Meyer, M. R., Fredette, N. C., Barton, M. & Prossnitz, E. R. Regulation of vascular smooth muscle tone by adipose-derived contracting factor. PLoS ONE 8, e79245 (2013).

pubmed: 24244459 doi: 10.1371/journal.pone.0079245 pmcid: 3823600

Meyer, M. R. et al. G protein-coupled estrogen receptor protects from atherosclerosis. Sci. Rep. 4, 7564 (2014).

pubmed: 25532911 doi: 10.1038/srep07564 pmcid: 4274506

Bopassa, J. C., Eghbali, M., Toro, L. & Stefani, E. A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 298, H16–23 (2010). First study reporting a protective role of GPER in myocardial reperfusion injury from myocardial ischaemia following coronary occlusion.

pubmed: 19880667 doi: 10.1152/ajpheart.00588.2009

Kabir, M. E. et al. G protein-coupled estrogen receptor 1 mediates acute estrogen-induced cardioprotection via MEK/ERK/GSK-3β pathway after ischemia/reperfusion. PLoS ONE 10, e0135988 (2015).

pubmed: 26356837 doi: 10.1371/journal.pone.0135988 pmcid: 4565659

Feng, Y., Madungwe, N. B., da Cruz Junho, C. V. & Bopassa, J. C. Activation of G protein-coupled oestrogen receptor 1 at the onset of reperfusion protects the myocardium against ischemia/reperfusion injury by reducing mitochondrial dysfunction and mitophagy. Br. J. Pharmacol. 174, 4329–4344 (2017).

pubmed: 28906548 doi: 10.1111/bph.14033 pmcid: 5715577

Iorga, A. et al. Rescue of pressure overload-induced heart failure by estrogen therapy. J. Am. Heart Assoc. 5, e002482 (2016).

pubmed: 26802104 doi: 10.1161/JAHA.115.002482 pmcid: 4859364

Goncalves, G. K. et al. Neonatal cardiomyocyte hypertrophy induced by endothelin-1 is blocked by estradiol acting on GPER. Am. J. Physiol. Cell Physiol. 314, C310–C322 (2018).

pubmed: 29167148 doi: 10.1152/ajpcell.00060.2017

Watanabe, T. et al. 17β-Estradiol inhibits cardiac fibroblast growth through both subtypes of estrogen receptor. Biochem. Biophys. Res. Commun. 311, 454–459 (2003).

pubmed: 14592435 doi: 10.1016/j.bbrc.2003.09.232

Mercier, I., Mader, S. & Calderone, A. Tamoxifen and ICI 182,780 negatively influenced cardiac cell growth via an estrogen receptor-independent mechanism. Cardiovasc. Res. 59, 883–892 (2003).

pubmed: 14553828 doi: 10.1016/S0008-6363(03)00517-0

Recchia, A. G. et al. The G protein-coupled receptor 30 is up-regulated by hypoxia-inducible factor-1α (HIF-1α) in breast cancer cells and cardiomyocytes. J. Biol. Chem. 286, 10773–10782 (2011).

pubmed: 21266576 doi: 10.1074/jbc.M110.172247 pmcid: 3060528

Whitcomb, V. et al. Regulation of beta adrenoceptor-mediated myocardial contraction and calcium dynamics by the G protein-coupled estrogen receptor 1. Biochem. Pharmacol. 171, 113727 (2020).

pubmed: 31759979 doi: 10.1016/j.bcp.2019.113727

Wang, H., Sun, X., Hodge, H. S., Ferrario, C. M. & Groban, L. NLRP3 inhibition improves heart function in GPER knockout mice. Biochem. Biophys. Res. Commun. 514, 998–1003 (2019). This study reports that inhibition of the NLRP3 inflammasome ameliorates impaired systolic and diastolic myocardial function in mice lacking GPER.

pubmed: 31092335 doi: 10.1016/j.bbrc.2019.05.045 pmcid: 6545146

Wang, H. et al. Activation of GPR30 attenuates diastolic dysfunction and left ventricle remodelling in oophorectomized mRen2.Lewis rats. Cardiovasc. Res. 94, 96–104 (2012).

pubmed: 22328091 doi: 10.1093/cvr/cvs090 pmcid: 3307382

Jessup, J. A., Lindsey, S. H., Wang, H., Chappell, M. C. & Groban, L. Attenuation of salt-induced cardiac remodeling and diastolic dysfunction by the GPER agonist G-1 in female mRen2.Lewis rats. PLoS ONE 5, e15433 (2010). The first report to suggest that pharmacological activation of GPER reduces functional and structural cardiac injury in salt-sensitive hypertension.

pubmed: 21082029 doi: 10.1371/journal.pone.0015433 pmcid: 2972725

Alencar, A. K. et al. Effect of age, estrogen status, and late-life GPER activation on cardiac structure and function in the Fischer344xBrown Norway female rat. J. Gerontol. A Biol. Sci. Med. Sci. 72, 152–162 (2017).

pubmed: 27006078 doi: 10.1093/gerona/glw045

Bairey Merz, C. N. et al. Sex and the kidneys: current understanding and research opportunities. Nat. Rev. Nephrol. 15, 776–783 (2019).

pubmed: 31586165 doi: 10.1038/s41581-019-0208-6

Chang, Y. et al. G protein-coupled estrogen receptor activation improves contractile and diastolic functions in rat renal interlobular artery to protect against renal ischemia reperfusion injury. Biomed. Pharmacother. 112, 108666 (2019).

pubmed: 30784936 doi: 10.1016/j.biopha.2019.108666

Hofmeister, M. V. et al. 17β-Estradiol induces nongenomic effects in renal intercalated cells through G protein-coupled estrogen receptor 1. Am. J. Physiol. Ren. Physiol. 302, F358–368 (2012).

doi: 10.1152/ajprenal.00343.2011

Gohar, E. Y. & Pollock, D. M. Functional interaction of endothelin receptors in mediating natriuresis evoked by G protein-coupled estrogen receptor 1. J. Pharmacol. Exp. Ther. 376, 98–105 (2021).

pubmed: 33127751 doi: 10.1124/jpet.120.000322 pmcid: 7788354

Meyer, M. R. et al. GPER is required for age-dependent albuminuria and glomerulosclerosis: evidence for its role in podocyte injury and mesangial Nox1 regulation. Hypertension 72, AP261 (2018).

doi: 10.1161/hyp.72.suppl_1.P261

Meyer, M. R. et al. Deletion of GPER protects from age-related renovascular dysfunction and tubulo-interstitial injury. Hypertension 66, AP607 (2015).

doi: 10.1161/hyp.66.suppl_1.p607

Qiao, C., Ye, W., Li, S., Wang, H. & Ding, X. Icariin modulates mitochondrial function and apoptosis in high glucose-induced glomerular podocytes through G protein-coupled estrogen receptors. Mol. Cell. Endocrinol. 473, 146–155 (2018).

pubmed: 29373840 doi: 10.1016/j.mce.2018.01.014

Lindsey, S. H., Yamaleyeva, L. M., Brosnihan, K. B., Gallagher, P. E. & Chappell, M. C. Estrogen receptor GPR30 reduces oxidative stress and proteinuria in the salt-sensitive female mRen2.Lewis rat. Hypertension 58, 665–671 (2011). The first study to report the antiproteinuric effects of pharmacological activation of GPER.

pubmed: 21844484 doi: 10.1161/HYPERTENSIONAHA.111.175174

Gohar, E. Y. et al. Activation of G protein-coupled estrogen receptor 1 ameliorates proximal tubular injury and proteinuria in Dahl salt-sensitive female rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 320, R297–R306 (2021).

pubmed: 33407017 doi: 10.1152/ajpregu.00267.2020 pmcid: 7988769

Sanchez, D. S. et al. Estradiol stimulates cell proliferation via classic estrogen receptor-alpha and G protein-coupled estrogen receptor-1 in human renal tubular epithelial cell primary cultures. Biochem. Biophys. Res. Commun. 512, 170–175 (2019).

pubmed: 30879772 doi: 10.1016/j.bbrc.2019.03.056

Kurt, A. H., Bozkus, F., Uremis, N. & Uremis, M. M. The protective role of G protein-coupled estrogen receptor 1 (GPER-1) on methotrexate-induced nephrotoxicity in human renal epithelium cells. Ren. Fail. 38, 686–692 (2016).

pubmed: 26981789 doi: 10.3109/0886022X.2016.1155398

Hutchens, M. P., Fujiyoshi, T., Komers, R., Herson, P. S. & Anderson, S. Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo. Am. J. Physiol. Ren. Physiol. 303, F377–385 (2012).

doi: 10.1152/ajprenal.00354.2011

Tofovic, S. P., Zhang, X., Jackson, E. K., Zhu, H. & Petrusevska, G. 2-Methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats. Vasc. Pharmacol. 51, 190–197 (2009).

doi: 10.1016/j.vph.2009.06.002

Umar, S. et al. Estrogen rescues preexisting severe pulmonary hypertension in rats. Am. J. Respir. Crit. Care Med. 184, 715–723 (2011).

pubmed: 21700911 doi: 10.1164/rccm.201101-0078OC pmcid: 3208600

Alencar, A. K. N. et al. Cardioprotection induced by activation of GPER in ovariectomized rats with pulmonary hypertension. J. Gerontol. A Biol. Sci. Med. Sci. 73, 1158–1166 (2018).

pubmed: 29790948 doi: 10.1093/gerona/gly068 pmcid: 6093348

Alencar, A. K. et al. Activation of GPER ameliorates experimental pulmonary hypertension in male rats. Eur. J. Pharm. Sci. 97, 208–217 (2017). This is the first study to report therapeutic efficacy and protection of the right ventricle of the heart by pharmacological activation of GPER in experimental pulmonary arterial hypertension.

pubmed: 27836751 doi: 10.1016/j.ejps.2016.11.009

Ahmadian, R. et al. GPER contributes to the development of pulmonary hypertension in female rats. FASEB J. 34, 1 (2020).

Meyer, M. R. & Barton, M. GPER blockers as Nox downregulators: a new drug class to target chronic non-communicable diseases. J. Steroid Biochem. Mol. Biol. 176, 82–87 (2018).

pubmed: 28343901 doi: 10.1016/j.jsbmb.2017.03.019

Mauvais-Jarvis, F., Clegg, D. J. & Hevener, A. L. The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 (2013). A comprehensive review of oestrogen receptor-dependent and GPER-dependent regulation glucose homeostasis and energy balance.

pubmed: 23460719 doi: 10.1210/er.2012-1055 pmcid: 3660717

Meyer, M. R., Clegg, D. J., Prossnitz, E. R. & Barton, M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol. 203, 259–269 (2011).

doi: 10.1111/j.1748-1716.2010.02237.x

Madak-Erdogan, Z. et al. Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. Sci. Signal. 9, ra53 (2016). This study reports the identification of ‘pathway-preferential’ oestrogens with beneficial vascular and metabolic effects without stimulating reproductive tissues.

pubmed: 27221711 doi: 10.1126/scisignal.aad8170 pmcid: 4896643

Gurney, E. P., Nachtigall, M. J., Nachtigall, L. E. & Naftolin, F. The Women’s Health Initiative Trial and related studies: 10 years later: a clinician’s view. J. Steroid Biochem. Mol. Biol. 142, 4–11 (2014).

pubmed: 24172877 doi: 10.1016/j.jsbmb.2013.10.009

Stubbins, R. E., Holcomb, V. B., Hong, J. & Nunez, N. P. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur. J. Nutr. 51, 861–870 (2012).

pubmed: 22042005 doi: 10.1007/s00394-011-0266-4

Bonds, D. E. et al. The effect of conjugated equine oestrogen on diabetes incidence: the women’s health initiative randomised trial. Diabetologia 49, 459–468 (2006).

pubmed: 16440209 doi: 10.1007/s00125-005-0096-0

Mårtensson, U. E. et al. Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice. Endocrinology 150, 687–698 (2009).

pubmed: 18845638 doi: 10.1210/en.2008-0623

Davis, K. E. et al. Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Horm. Behav. 66, 196–207 (2014).

pubmed: 24560890 doi: 10.1016/j.yhbeh.2014.02.004 pmcid: 4051842

Le May, C. et al. Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc. Natl Acad. Sci. USA 103, 9232–9237 (2006).

pubmed: 16754860 doi: 10.1073/pnas.0602956103 pmcid: 1482595

Liu, S. et al. Importance of extranuclear estrogen receptor-α and membrane G protein-coupled estrogen receptor in pancreatic islet survival. Diabetes 58, 2292–2302 (2009).This study is the first to report a role of GPER in the regulation of pancreatic islet survival.

pubmed: 19587358 doi: 10.2337/db09-0257 pmcid: 2750222

Sharma, G. et al. Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes. Sci. Transl Med. 12, eaau5956 (2020). The study reports efficacy of the GPER agonist G-1 for the treatment of obesity, and the associated insulin resistance and diabetes mellitus.

pubmed: 31996464 doi: 10.1126/scitranslmed.aau5956 pmcid: 7083206

Butler, M. J., Hildebrandt, R. P. & Eckel, L. A. Selective activation of estrogen receptors, ERα and GPER-1, rapidly decreases food intake in female rats. Horm. Behav. 103, 54–61 (2018).

pubmed: 29807036 doi: 10.1016/j.yhbeh.2018.05.018 pmcid: 6076327

Azizian, H., Khaksari, M., Asadi Karam, G., Esmailidehaj, M. & Farhadi, Z. Cardioprotective and anti-inflammatory effects of G-protein coupled receptor 30 (GPR30) on postmenopausal type 2 diabetic rats. Biomed. Pharmacother. 108, 153–164 (2018).

pubmed: 30218860 doi: 10.1016/j.biopha.2018.09.028

Balhuizen, A., Kumar, R., Amisten, S., Lundquist, I. & Salehi, A. Activation of G protein-coupled receptor 30 modulates hormone secretion and counteracts cytokine-induced apoptosis in pancreatic islets of female mice. Mol. Cell. Endocrinol. 320, 16–24 (2010).

pubmed: 20122988 doi: 10.1016/j.mce.2010.01.030

Kumar, R., Balhuizen, A., Amisten, S., Lundquist, I. & Salehi, A. Insulinotropic and antidiabetic effects of 17β-estradiol and the GPR30 agonist G-1 on human pancreatic islets. Endocrinology 152, 2568–2579 (2011).

pubmed: 21521748 doi: 10.1210/en.2010-1361

Jacenik, D., Beswick, E. J., Krajewska, W. M. & Prossnitz, E. R. G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis. World J. Gastroenterol. 25, 4092–4104 (2019).

pubmed: 31435166 doi: 10.3748/wjg.v25.i30.4092 pmcid: 6700692

Hata, M. et al. GPR30-expressing gastric chief cells do not dedifferentiate but are eliminated via PDK-dependent cell competition during development of metaplasia. Gastroenterology 158, 1650–1666.e15 (2020).

pubmed: 32032583 doi: 10.1053/j.gastro.2020.01.046

Tsai, C. C. et al. Estradiol mediates relaxation of porcine lower esophageal sphincter. Steroids 136, 56–62 (2018).

pubmed: 29733860 doi: 10.1016/j.steroids.2018.05.001

Zielinska, M. et al. G protein-coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain. Neurogastroenterol. Motil. 29, 13025 (2017).

doi: 10.1111/nmo.13025

Li, Y. et al. G protein-coupled estrogen receptor is involved in modulating colonic motor function via nitric oxide release in C57BL/6 female mice. Neurogastroenterol. Motil. 28, 432–442 (2016).

pubmed: 26661936 doi: 10.1111/nmo.12743

Jacenik, D. et al. G protein-coupled estrogen receptor mediates anti-inflammatory action in Crohn’s disease. Sci. Rep. 9, 6749 (2019). This study reports that pharmacological activation of GPER reduces inflammatory activation and mortality in experimental Crohn’s disease.

pubmed: 31043642 doi: 10.1038/s41598-019-43233-3 pmcid: 6494840

Wlodarczyk, M. et al. G protein-coupled receptor 30 (GPR30) expression pattern in inflammatory bowel disease patients suggests its key role in the inflammatory process. A preliminary study. J. Gastrointestin. Liver. Dis. 26, 29–35 (2017).

pubmed: 28338111 doi: 10.15403/jgld.2014.1121.261.gpr

Qin, B. et al. Expression of G protein-coupled estrogen receptor in irritable bowel syndrome and its clinical significance. Int. J. Clin. Exp. Pathol. 7, 2238–2246 (2014).

pubmed: 24966932 pmcid: 4069936

Shao, X., Li, J., Xu, F., Chen, D. & Liu, K. Mir-155-mediated deregulation of GPER1 plays an important role in the gender differences related to inflammatory bowel disease. Can. J. Infect. Dis. Med. Microbiol. 2020, 8811477 (2020).

pubmed: 33014211 doi: 10.1155/2020/8811477 pmcid: 7516711

Jacenik, D. et al. Estrogen signaling deregulation related with local immune response modulation in irritable bowel syndrome. Mol. Cell. Endocrinol. 471, 89–96 (2018).

pubmed: 28774781 doi: 10.1016/j.mce.2017.07.036

Chai, S. et al. Activation of G protein-coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation. Clin. Sci. 133, 449–464 (2019).

doi: 10.1042/CS20180919

Wang, Q. et al. Activation of the G protein-coupled estrogen receptor prevented the development of acute colitis by protecting the crypt cell. J. Pharmacol. Exp. Ther. 376, 281–293 (2021).

pubmed: 33318078 doi: 10.1124/jpet.120.000216

Chaturantabut, S. et al. Estrogen activation of G-protein-coupled estrogen receptor 1 regulates phosphoinositide 3-kinase and mTOR signaling to promote liver growth in zebrafish and proliferation of human hepatocytes. Gastroenterology 156, 1788–1804.e13 (2019). An important paper reporting that pharmacological activation of GPER stimulates hepatocyte proliferation and thus liver regeneration.

pubmed: 30641053 doi: 10.1053/j.gastro.2019.01.010

Tian, L. et al. The developmental wnt signaling pathway effector β-catenin/TCF mediates hepatic functions of the sex hormone estradiol in regulating lipid metabolism. PLoS Biol. 17, e3000444 (2019).

pubmed: 31589598 doi: 10.1371/journal.pbio.3000444 pmcid: 6797220

Farruggio, S. et al. Genistein improves viability, proliferation and mitochondrial function of cardiomyoblasts cultured in physiologic and peroxidative conditions. Int. J. Mol. Med. 44, 2298–2310 (2019).

pubmed: 31638174

Wang, H. H., Liu, M., Clegg, D. J., Portincasa, P. & Wang, D. Q. New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation. Biochim. Biophys. Acta 1791, 1037–1047 (2009).

pubmed: 19589396 doi: 10.1016/j.bbalip.2009.06.006 pmcid: 2756670

de Bari, O., Wang, T. Y., Liu, M., Portincasa, P. & Wang, D. Q. Estrogen induces two distinct cholesterol crystallization pathways by activating ERα and GPR30 in female mice. J. Lipid Res. 56, 1691–1700 (2015).

pubmed: 26152119 doi: 10.1194/jlr.M059121 pmcid: 4548773

Wang, H. H. et al. Activation of a novel estrogen receptor GPR30 enhances cholesterol cholelithogenesis in female mice. Hepatology 72, 2077–2089 (2020). This study causally links GPER to oestrogen-dependent gallstone formation in female mice.

pubmed: 32112420 doi: 10.1002/hep.31212

Filardo, E. J. et al. Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin. Cancer Res. 12, 6359–6366 (2006). The first report showing an association between GPER expression and clinical outcome in breast cancer.

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Ignatov, T., Treeck, O., Kalinski, T., Ortmann, O. & Ignatov, A. GPER-1 expression is associated with a decreased response rate to primary tamoxifen therapy of breast cancer patients. Arch. Gynecol. Obstet. 301, 565–571 (2020).

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Ignatov, T. et al. G-protein-coupled estrogen receptor GPER-1 expression in hormone receptor-positive breast cancer is associated with poor benefit of tamoxifen. Breast Cancer Res. Treat. 174, 121–127 (2019).

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Pepermans, R. A., Sharma, G. & Prossnitz, E. R. G protein-coupled estrogen receptor in cancer and stromal cells: functions and novel therapeutic perspectives. Cells 10, 672 (2021).

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De Francesco, E. M. et al. GPER mediates activation of HIF1α/VEGF signaling by estrogens. Cancer Res. 74, 4053–4064 (2014).

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Smith, H. O. et al. GPR30: a novel indicator of poor survival for endometrial carcinoma. Am. J. Obstet. Gynecol. 196 (386), e381–e389 (2007). This study was the first to suggest an association between GPER expression and clinical outcome and survival in patients with endometrial cancer.

Smith, H. O. et al. GPR30 predicts poor survival for ovarian cancer. Gynecol. Oncol. 114, 465–471 (2009). This study was the first to suggest an association between GPER expression and clinical outcome and survival in patients with ovarian cancer.

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Chan, Q. K. et al. Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest. Cell. Death Differ. 17, 1511–1523 (2010).

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Natale, C. A. et al. Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma. Cell. Mol. Gastroenterol. Hepatol. 10, 868–880 (2020). This study reports that pharmacological activation of GPER enhances the efficacy of immune checkpoint inhibitors (ICIs) and prolongs survival in a model of pancreatic cancer.

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Vivacqua, A. et al. 17β-Estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the G protein-coupled receptor GPR30. Mol. Pharmacol. 70, 1414–1423 (2006).

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Gilligan, L. C. et al. Estrogen activation by steroid sulfatase increases colorectal cancer proliferation via GPER. J. Clin. Endocrinol. Metab. 102, 4435–4447 (2017).

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Liu, C. et al. G-protein-coupled estrogen receptor antagonist G15 decreases estrogen-induced development of non-small cell lung cancer. Oncol. Res. 27, 283–292 (2019).

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Scaling, A. L., Prossnitz, E. R. & Hathaway, H. J. GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast. Horm. Cancer 5, 146–160 (2014).

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Vivacqua, A. et al. The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17β-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol. Endocrinol. 20, 631–646 (2006).

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Albanito, L. et al. G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17β-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res. 67, 1859–1866 (2007).

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Natale, C. A. et al. Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade. eLife 7, e31770 (2018). This study reports that pharmacological activation of GPER enhances the efficacy of ICI and prolongs survival in a mouse model of malignant melanoma.

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Wei, T. et al. G protein-coupled estrogen receptor deficiency accelerates liver tumorigenesis by enhancing inflammation and fibrosis. Cancer Lett. 382, 195–202 (2016).

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Ignatov, A. et al. G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer. Breast Cancer Res. Treat. 128, 457–466 (2011).

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Marjon, N. A., Hu, C., Hathaway, H. J. & Prossnitz, E. R. G protein-coupled estrogen receptor regulates mammary tumorigenesis and metastasis. Mol. Cancer Res. 12, 1644–1654 (2014).

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Li, Y. et al. 4-Hydroxytamoxifen-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. Toxicology 309, 61–65 (2013).

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Catalano, S. et al. Tamoxifen through GPER upregulates aromatase expression: a novel mechanism sustaining tamoxifen-resistant breast cancer cell growth. Breast Cancer Res. Treat. 146, 273–285 (2014).

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Liu, Y. et al. G15 sensitizes epithelial breast cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of GPR30. Am. J. Transl Res. 7, 967–975 (2015).

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Santolla, M. F. et al. GPER mediates a feedforward FGF2/FGFR1 paracrine activation coupling CAFs to cancer cells toward breast tumor progression. Cells 8, 223 (2019).

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De Marco, P. et al. GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response. Sci. Rep. 6, 24354 (2016). This study provides evidence for a role of GPER in inflammatory signalling in breast cancer in cancer-associated fibroblasts.

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Divella, R., De Luca, R., Abbate, I., Naglieri, E. & Daniele, A. Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation. J. Cancer 7, 2346–2359 (2016).

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Costa, A. J. et al. Overexpression of estrogen receptor GPER1 and G1 treatment reduces SARS-CoV-2 infection in BEAS-2B bronchial cells. Mol. Cell. Endocrinol. 558, 111775 (2022).

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Wang, C. et al. Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1. J. Immunol. 182, 3294–3303 (2009). One of two studies to first suggest a role for GPER in multiple sclerosis.

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Du, Z. R. et al. G protein-coupled estrogen receptor is involved in the anti-inflammatory effects of genistein in microglia. Phytomedicine 43, 11–20 (2018).

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Guan, J., Yang, B., Fan, Y. & Zhang, J. GPER agonist G1 attenuates neuroinflammation and dopaminergic neurodegeneration in parkinson disease. Neuroimmunomodulation 24, 60–66 (2017).

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Harding, A. T., Goff, M. A., Froggatt, H. M., Lim, J. K. & Heaton, N. S. GPER1 is required to protect fetal health from maternal inflammation. Science 371, 271–276 (2021). This study reveals a crucial immune regulatory role for GPER in protecting the fetus from maternal inflammation and infection.

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Meyer, M. R., Fredette, N. C., Sharma, G., Barton, M. & Prossnitz, E. R. GPER is required for the age-dependent upregulation of the myocardial endothelin system. Life Sci. 159, 61–65 (2016).

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Murata, T., Dietrich, H. H., Xiang, C. & Dacey, R. G. Jr. G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats. Stroke 44, 779–785 (2013).

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Han, Z. W. et al. GPER agonist G1 suppresses neuronal apoptosis mediated by endoplasmic reticulum stress after cerebral ischemia/reperfusion injury. Neural Regen. Res. 14, 1221–1229 (2019).

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Zhang, B. et al. Estradiol and G1 reduce infarct size and improve immunosuppression after experimental stroke. J. Immunol. 184, 4087–4094 (2010). The first study to suggest protective effects of GPER activation in a preclinical model of ischaemic stroke.

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Zheng, Y. et al. GPER-deficient rats exhibit lower serum corticosterone level and increased anxiety-like behavior. Neural Plast. 2020, 8866187 (2020).

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Kubota, T., Matsumoto, H. & Kirino, Y. Ameliorative effect of membrane-associated estrogen receptor G protein coupled receptor 30 activation on object recognition memory in mouse models of Alzheimer’s disease. J. Pharmacol. Sci. 131, 219–222 (2016).

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The G protein-coupled oestrogen receptor GPER in health and disease: an update.

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Eric R Prossnitz (ER)

Matthias Barton (M)

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