Is the membrane estrogen receptor, GPER1, a promiscuous receptor that modulates nuclear estrogen receptor-mediated functions in the brain?

Vajaria, Ruby; Vasudevan, Nandini

doi:10.1016/j.yhbeh.2018.06.012

Cited by 29 publications

(24 citation statements)

References 93 publications

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“…Our results show that inhibition of estradiol synthesis in the brain results in a decrease in ERE-dependent transcription, demonstrating a role for neuroestrogen regulation of the genomic effects of estrogen receptors in addition to the established nongenomic membrane effects. These findings are consistent with the previously suggested hypothesis (Cornil, 2018; Vajaria and Vasudevan, 2018) that the activation of membrane estrogen receptors by neuroestrogens may ultimately lead to transcriptional activity of nuclear estrogen receptors through the activation of various signaling cascades.…”

Section: Discussionsupporting

confidence: 93%

Neuroestrogen-Dependent Transcriptional Activity in the Brains of ERE-Luciferase Reporter Mice following Short- and Long-Term Ovariectomy

Baumgartner

Grissom

Pollard

et al. 2019

eNeuro

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Section: Discussionsupporting

confidence: 93%

Neuroestrogen-Dependent Transcriptional Activity in the Brains of ERE-Luciferase Reporter Mice following Short- and Long-Term Ovariectomy

Baumgartner

Grissom

Pollard

et al. 2019

eNeuro

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“…In this regard, recent studies have demonstrated that, in different cellular systems, GPER1 and ERα can cross‐talk with each other, highlighting the role of GPER1 as a modulator of classical oestrogen receptors . Indeed, GPER1 signalling appeared to be either synergic or antagonistic for the final output of oestrogenic, ER‐mediated, action . Interestingly, ERα is reported to require GPER1 to mediate the neuroprotective actions of oestradiol on dopaminergic neurones in a mouse model of Parkinson's disease …”

Section: Discussionmentioning

confidence: 99%

The G protein‐coupled oestrogen receptor, GPER1, mediates direct anti‐inflammatory effects of oestrogens in human cholinergic neurones from the nucleus basalis of Meynert

Sarchielli

Guarnieri

Idrizaj

et al. 2020

J Neuroendocrinology

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It has been well established, particularly in animal models, that oestrogens exert neuroprotective effects in brain areas linked to cognitive processes. A key protective role could reside in the capacity of oestrogen to modulate the inflammatory response. However, the direct neuroprotective actions of oestrogens on neurones are complex and remain to be fully clarified. In the present study, we took advantage of a previously characterised primary culture of human cholinergic neurones (hfNBM) from the foetal nucleus basalis of Meynert, which is known to regulate hippocampal and neocortical learning and memory circuits, aiming to investigate the direct effects of oestrogens under inflammatory conditions. Exposure of cells to tumour necrosis factor (TNF)α (10 ng mL‐1) determined the activation of an inflammatory response, as demonstrated by nuclear factor‐kappa B p65 nuclear translocation and cyclooxygenase‐2 mRNA expression. These effects were inhibited by treatment with either 17β‐oestradiol (E2) (10 nmol L‐1) or G1 (100 nmol L‐1), the selective agonist of the G protein‐coupled oestrogen receptor (GPER1). Interestingly, the GPER1 antagonist G15 abolished the effects of E2 in TNFα‐treated cells, whereas the ERα/ERβ inhibitor tamoxifen did not. Electrophysiological measurements in hfNBMs revealed a depolarising effect caused by E2 that was specifically blocked by tamoxifen and not by G15. Conversely, G1 specifically hyperpolarised the cell membrane and also increased both inward and outward currents elicited by a depolarising stimulus, suggesting a modulatory action on hfNBM excitability by GPER1 activation. Interestingly, pretreating cells with TNFα completely blocked the effects of G1 on membrane properties and also significantly reduced GPER1 mRNA expression. In addition, we found a peculiar subcellular localisation of GPER1 to focal adhesion sites that implicates new possible mechanisms of action of GPER1 in the neuronal perception of mechanical stimuli. The results obtained in the present study indicate a modulatory functional role of GPER1 with respect to mediating the oestrogen neuroprotective effect against inflammation in brain cholinergic neurones and, accordingly, may help to identify protective strategies for preventing cognitive impairments.

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“…GPER1 activation is now well-known for inducing protective effects in several disease models, including I/R injury, hypertension (4-6), Parkinson's disease (23), retinal ganglion degeneration (74), and breast cancer (75). In fact, GPER1 activation has been reported to exert protective effects against harmful effects in several other organs, including the heart (4-6), brain (21,76), muscle (77), testes (77), intestine (26), and kidney (78). Using isolated perfused heart model, others and we have reported that acute (∼1 h) pre-ischemic E2 treatment induces cardioprotective effects against I/R injury through GPER1 activation (4)(5)(6)(7)(8).…”

Section: Discussionmentioning

confidence: 99%

“…Besides these effects mediated through its two steroidal ERs, a complementary but separate mode of rapid E2 actions have been reported that depend on agonist activation of the membrane-bound GPER1. GPER1 is highly expressed in almost all the organs, including the myocardium (13,20), brain (21), kidney (22), and myometrium (23). Although E2's genomic mechanisms via the nuclear ERs are now well-characterized, those predominantly mediated by GPER1 activation still need to be explored.…”

Section: Introductionmentioning

confidence: 99%

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

et al. 2020

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Introduction: Estrogen (17β-estradiol, E2) is well-known to induce cardioprotective effects against ischemia/reperfusion (I/R) injury. We recently reported that acute application of E2 at the onset of reperfusion in vivo induces cardioprotective effects against I/R injury via activation of its non-steroidal receptor, G protein-coupled estrogen receptor 1 (GPER1). Here, we investigated the impact and mechanism underlying chronic GPER1 activation in cultured H9c2 rat cardiomyoblasts. Methods: H9c2 rat cardiomyoblasts were cultured and pretreated with the cytotoxic agent H 2 O 2 for 24 h and incubated in the presence of vehicle (control), GPER1 agonists E2 and G1, or GPER1 agonists supplemented with G15 (GPER1 antagonist) for 48 or 96 h. After treatment, cells were collected to measure the rate of cell death and viability using flow cytometry and Calcein AM assay or MTT assay, respectively. The resistance to opening of the mitochondrial permeability transition pore (mPTP), the mitochondrial membrane potential, and ATP production was assessed using fluorescence microscopy, and the mitochondrial structural integrity was observed with electron microscopy. The levels of the phosphorylation of mammalian sterile-20-like kinase (MST1) and yes-associated protein (YAP) were assessed by Western blot analysis in whole-cell lysate, while the expression levels of mitochondrial biogenesis genes, YAP target genes, and proapoptotic genes were measured by qRT-PCR. Results: We found that after H 2 O 2 treatment, chronic E2/G1 treatment decreased cell death effect was associated with the prevention of the S phase of the cell cycle arrest compared to control. In the mitochondria, chronic E2/G1 activation treatment preserved the cristae morphology, and increased resistance to opening of mPTP, but Imam Aliagan et al. Chronic GPER1 Actions and Cell Death with little change to mitochondrial fusion/fission. Additionally, chronic E2/G1 treatment predominantly reduced phosphorylation of MST1 and YAP, as well as increased MST1 and YAP protein levels. E2 treatment also upregulated the expression levels of TGFβ and PGC-1α mRNAs and downregulated PUMA and Bim mRNAs. Except for ATP production, all the E2 or G1 effects were prevented by the cotreatment with the GPER1 antagonist, G15. Conclusion: Together, these results indicate that chronic GPER1 activation with its agonists E2 or G1 treatment protects H9c2 cardiomyoblasts against oxidative stressinduced cell death and increases cell viability by preserving mitochondrial structure and function as well as delaying the opening of mPTP. These chronic GPER1 effects are associated with the deactivation of the non-canonical MST1/YAP mechanism that leads to genetic upregulation of cell growth genes (CTGF, CYR61, PGC-1α, and ANKRD1), and downregulation of proapoptotic genes (PUMA and Bim).

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Is the membrane estrogen receptor, GPER1, a promiscuous receptor that modulates nuclear estrogen receptor-mediated functions in the brain?

Cited by 29 publications

References 93 publications

Neuroestrogen-Dependent Transcriptional Activity in the Brains of ERE-Luciferase Reporter Mice following Short- and Long-Term Ovariectomy

Neuroestrogen-Dependent Transcriptional Activity in the Brains of ERE-Luciferase Reporter Mice following Short- and Long-Term Ovariectomy

The G protein‐coupled oestrogen receptor, GPER1, mediates direct anti‐inflammatory effects of oestrogens in human cholinergic neurones from the nucleus basalis of Meynert

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

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