scholarly journals G protein-coupled estrogen receptor regulates heart rate by modulating thyroid hormone levels in zebrafish embryos

2016 ◽  
Author(s):  
Shannon N Romano ◽  
Hailey E Edwards ◽  
Xiangqin Cui ◽  
Daniel A Gorelick
Keyword(s):  
Heart Rate ◽  
Estrogen Receptor ◽  
Thyroid Hormone ◽  
G Protein ◽  
Sex Differentiation ◽  
Zebrafish Embryos ◽  
Basal Heart Rate ◽  
Normal Heart Rate ◽  
G Protein Coupled

AbstractEstrogens act by binding to estrogen receptors alpha and beta (ERα, ERβ), ligand-dependent transcription factors that play crucial roles in sex differentiation, tumor growth and cardiovascular physiology. Estrogens also activate the G protein-coupled estrogen receptor (GPER), however the function of GPER in vivo is less well understood. Here we find that GPER is required for normal heart rate in zebrafish embryos. Acute exposure to estrogens increased heart rate in wildtype and in ERα and ERβ mutant embryos but not in GPER mutants. GPER mutant embryos exhibited reduced basal heart rate, while heart rate was normal in ERα and ERβ mutants. We detected gper transcript in discrete regions of the brain and pituitary but not in the heart, suggesting that GPER acts centrally to regulate heart rate. In the pituitary, we observed gper expression in cells that regulate levels of thyroid hormone triiodothyronine (T3), a hormone known to increase heart rate. GPER mutant embryos showed a mean 50% reduction in T3 levels compared to wildtype, while exposure to exogenous T3 rescued the reduced heart rate phenotype in GPER mutants. Our results demonstrate that estradiol plays a previously unappreciated role in the acute modulation of heart rate during zebrafish embryonic development and suggest that GPER regulates basal heart rate by altering total T3 levels.

scholarly journals The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1

2016 ◽  
Vol 41 (12) ◽  
pp. 1303-1310 ◽  
Author(s):  
Guan-Yu Ren ◽  
Chun-Yang Chen ◽  
Wei-Guo Chen ◽  
Ya Huang ◽  
Li-Qiang Qin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Estrogen Receptor ◽  
Benign Prostatic Hyperplasia ◽  
G Protein ◽  
Therapeutic Potential ◽  
Prostatic Hyperplasia ◽  
Docking Simulations ◽  
G Protein Coupled

Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.

scholarly journals BPA Directly Decreases GnRH Neuronal Activity via Noncanonical Pathway

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1980-1990 ◽  
Author(s):  
Ulrike Klenke ◽  
Stephanie Constantin ◽  
Susan Wray
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Neuronal Activity ◽  
Environmental Pollutant ◽  
Pcr Analysis ◽  
Gnrh Neurons ◽  
Noncanonical Pathway ◽  
G Protein Coupled ◽  
Estrogen Related Receptor

Abstract Peripheral feedback of gonadal estrogen to the hypothalamus is critical for reproduction. Bisphenol A (BPA), an environmental pollutant with estrogenic actions, can disrupt this feedback and lead to infertility in both humans and animals. GnRH neurons are essential for reproduction, serving as an important link between brain, pituitary, and gonads. Because GnRH neurons express several receptors that bind estrogen, they are potential targets for endocrine disruptors. However, to date, direct effects of BPA on GnRH neurons have not been shown. This study investigated the effects of BPA on GnRH neuronal activity using an explant model in which large numbers of primary GnRH neurons are maintained and express many of the receptors found in vivo. Because oscillations in intracellular calcium have been shown to correlate with electrical activity in GnRH neurons, calcium imaging was used to assay the effects of BPA. Exposure to 50μM BPA significantly decreased GnRH calcium activity. Blockage of γ-aminobutyric acid ergic and glutamatergic input did not abrogate the inhibitory BPA effect, suggesting direct regulation of GnRH neurons by BPA. In addition to estrogen receptor-β, single-cell RT-PCR analysis confirmed that GnRH neurons express G protein-coupled receptor 30 (G protein-coupled estrogen receptor 1) and estrogen-related receptor-γ, all potential targets for BPA. Perturbation studies of the signaling pathway revealed that the BPA-mediated inhibition of GnRH neuronal activity occurred independent of estrogen receptors, GPER, or estrogen-related receptor-γ, via a noncanonical pathway. These results provide the first evidence of a direct effect of BPA on GnRH neurons.

scholarly journals G protein-coupled estrogen receptor regulates embryonic heart rate in zebrafish

PLoS Genetics ◽  
2017 ◽  
Vol 13 (10) ◽  
pp. e1007069 ◽  
Author(s):  
Shannon N. Romano ◽  
Hailey E. Edwards ◽  
Jaclyn Paige Souder ◽  
Kevin J. Ryan ◽  
Xiangqin Cui ◽  
...  
Keyword(s):  
Heart Rate ◽  
Estrogen Receptor ◽  
G Protein ◽  
Embryonic Heart ◽  
G Protein Coupled

scholarly journals G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Whitney K. Petrie ◽  
Megan K. Dennis ◽  
Chelin Hu ◽  
Donghai Dai ◽  
Jeffrey B. Arterburn ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Endometrial Cancer ◽  
Tumor Growth ◽  
G Protein ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Endometrial Tumor ◽  
Selective Ligands ◽  
G Protein Coupled

Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERαand ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activityin vivoprevents estrogen-mediated tumor growth.

scholarly journals The role of G-protein-coupled membrane estrogen receptor in mouse Leydig cell function—in vivo and in vitro evaluation

2018 ◽  
Vol 374 (2) ◽  
pp. 389-412 ◽  
Author(s):  
M. Kotula-Balak ◽  
P. Pawlicki ◽  
A. Milon ◽  
W. Tworzydlo ◽  
M. Sekula ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Leydig Cell ◽  
Cell Function ◽  
G Protein Coupled ◽  
Mouse Leydig Cell ◽  
Leydig Cell Function

scholarly journals G protein-coupled estrogen receptor is not required for sex determination or ovary function in zebrafish

2018 ◽  
Author(s):  
Camerron M. Crowder ◽  
Shannon N. Romano ◽  
Daniel A. Gorelick
Keyword(s):  
Estrogen Receptor ◽  
Sex Determination ◽  
G Protein ◽  
Oocyte Maturation ◽  
Ovary Development ◽  
Wild Type ◽  
Ovary Function ◽  
And Function ◽  
G Protein Coupled

ABSTRACTEstrogens regulate vertebrate development and function through binding to nuclear estrogen receptors alpha and beta (ERα, ERβ) and the G protein-coupled estrogen receptor (GPER). Studies in mutant animal models demonstrated that ERα and ERβ are required for normal ovary development and function. However, the degree to which GPER signaling contributes to ovary development and function is less well understood. Previous studies using cultured fish oocytes found that estradiol inhibits oocyte maturation in a GPER-dependent manner, but whether GPER regulates oocyte maturation in vivo is not known. To test the hypothesis that GPER regulates oocyte maturation in vivo, we assayed ovary development and function in gper mutant zebrafish. We found that homozygous mutant gper embryos developed into male and female adults with normal sex ratios and fertility. Adult mutant fish exhibited normal secondary sex characteristics and fertility. Additionally, mutant ovaries were histologically normal. We observed no differences in the number of immature versus mature oocytes in mutant versus wild-type ovaries from both young and aged adults. Furthermore, expression of genes associated with sex determination and ovary function were normal in gper mutant ovaries compared to wild type. Our findings suggest that GPER is not required for sex determination, ovary development or fertility in zebrafish.

scholarly journals Activation of G protein coupled estrogen receptor prevents chemotherapy-induced intestinal mucositis by inhibiting the DNA damage in crypt cell in an extracellular signal-regulated kinase 1- and 2- dependent manner

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Guanyu Chen ◽  
Honghui Zeng ◽  
Xinyun Li ◽  
Jianbo Liu ◽  
Zhao Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Estrogen Receptor ◽  
G Protein ◽  
Cyclin B1 ◽  
Crypt Cell ◽  
Mucosal Barrier ◽  
Dependent Manner ◽  
Intestinal Mucositis ◽  
G Protein Coupled

AbstractChemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL+ cells, Ki67+ and bromodeoxyuridine+ cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX+ cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.

Sign in / Sign up

Export Citation Format

Share Document