scholarly journals β-Arrestin-1 inhibits glucocorticoid receptor turnover and alters glucocorticoid signaling

2019 ◽  
Vol 294 (29) ◽  
pp. 11225-11239 ◽  
Author(s):  
Maria G. Petrillo ◽  
Robert H. Oakley ◽  
John A. Cidlowski
Keyword(s):  
Glucocorticoid Receptor ◽  
Glucocorticoid Signaling ◽  
Receptor Turnover

scholarly journals The Glucocorticoid Receptor in Cardiovascular Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1227 ◽  
Author(s):  
Liu ◽  
Zhang ◽  
Knight ◽  
Goodwin
Keyword(s):  
Glucocorticoid Receptor ◽  
Cardiovascular System ◽  
Gene Networks ◽  
Cardiovascular Health ◽  
Critical Role ◽  
Glucocorticoid Signaling ◽  
Health And Disease ◽  
Nuclear Receptor Family

The glucocorticoid receptor is a member of the nuclear receptor family that controls many distinct gene networks, governing various aspects of development, metabolism, inflammation, and the stress response, as well as other key biological processes in the cardiovascular system. Recently, research in both animal models and humans has begun to unravel the profound complexity of glucocorticoid signaling and convincingly demonstrates that the glucocorticoid receptor has direct effects on the heart and vessels in vivo and in vitro. This research has contributed directly to improving therapeutic strategies in human disease. The glucocorticoid receptor is activated either by the endogenous steroid hormone cortisol or by exogenous glucocorticoids and acts within the cardiovascular system via both genomic and non-genomic pathways. Polymorphisms of the glucocorticoid receptor are also reported to influence the progress and prognosis of cardiovascular disease. In this review, we provide an update on glucocorticoid signaling and highlight the critical role of this signaling in both physiological and pathological conditions of the cardiovascular system. With increasing in-depth understanding of glucocorticoid signaling, the future is promising for the development of targeted glucocorticoid treatments and improved clinical outcomes.

scholarly journals A novel non genomic glucocorticoid signaling mediated by a membrane palmitoylated glucocorticoid receptor cross talks with GnRH in gonadotrope cells

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Mohsen Ayrout ◽  
Violaine Simon ◽  
Valérie Bernard ◽  
Nadine Binart ◽  
Joëlle Cohen-Tannoudji ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Glucocorticoid Signaling

scholarly journals Disrupted Corticosterone Pulsatile Patterns Attenuate Responsiveness to Glucocorticoid Signaling in Rat Brain

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1177-1186 ◽  
Author(s):  
R. Angela Sarabdjitsingh ◽  
Sheena Isenia ◽  
Annelies Polman ◽  
Jona Mijalkovic ◽  
Servane Lachize ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Glucocorticoid Receptor ◽  
Rat Brain ◽  
Target Gene ◽  
Nuclear Translocation ◽  
Underlying Mechanism ◽  
Daily Average ◽  
Glucocorticoid Signaling ◽  
Hippocampal Area ◽  
Acute Challenge

Chronically elevated circulating glucocorticoid levels are although to enhance vulnerability to psychopathology. Here we hypothesized that such sustained glucocorticoid levels, disturbing corticosterone pulsatility, attenuate glucocorticoid receptor signaling and target gene responsiveness to an acute challenge in the rat brain. Rats were implanted with vehicle or 40 or 100% corticosterone pellets known to flatten ultradian and circadian rhythmicity while maintaining daily average levels or mimic pathological conditions. Additionally, recovery from constant exposure was studied in groups that had the pellet removed 24 h prior to the challenge. Molecular markers for receptor responsiveness (receptor levels, nuclear translocation, promoter occupancy, and target gene expression) to an acute challenge mimicking the stress response (3 mg/kg ip) were studied in the hippocampal area. Implantation of 40 and 100% corticosterone pellets dose-dependently down-regulated glucocorticoid receptor and attenuated mineralocorticoid receptor and glucocorticoid receptor translocation to the acute challenge. Interestingly, whereas target gene Gilz expression to the challenge was already attenuated by tonic daily average levels (40%), Sgk-1 was affected only after constant high corticosterone exposure (100%), indicating altered receptor responsiveness due to treatment. Washout of 100% corticosterone recovered all molecular markers (partial), whereas removal of the 40% corticosterone pellet still attenuated responsiveness to the challenge. We propose that corticosteroid pulsatility is crucial in maintaining normal responsiveness to glucocorticoids. Whereas the results with 100% corticosterone are likely attributed to receptor saturation, subtle changes in the pattern of exposure (40%) induces changes at least as severe for glucocorticoid signaling as overt hypercorticism, suggesting an underlying mechanism sensitive to the pattern of hormone exposure.

scholarly journals Natural Mating Differentially Triggers Expression of Glucocorticoid Receptor (NR3C1)-Related Genes in the Preovulatory Porcine Female Reproductive Tract

2020 ◽  
Vol 21 (12) ◽  
pp. 4437 ◽  
Author(s):  
Mateo Ruiz-Conca ◽  
Jaume Gardela ◽  
Cristina Alicia Martínez ◽  
Dominic Wright ◽  
Manel López-Bejar ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Signal Transducer ◽  
Hydroxysteroid Dehydrogenases ◽  
Glucocorticoid Signaling ◽  
Sperm Reservoir ◽  
Natural Mating ◽  
Harmful Effects ◽  
Nuclear Receptor Subfamily

Mating initiates dynamic modifications of gene transcription in the female reproductive tract, preparing the female for fertilization and pregnancy. Glucocorticoid signaling is essential for the homeostasis of mammalian physiological functions. This complex glucocorticoid regulation is mediated through the glucocorticoid receptor, also known as nuclear receptor subfamily 3 group C member 1 (NR3C1/GR) and related genes, like 11β-hydroxysteroid dehydrogenases (HSD11Bs) and the FK506-binding immunophilins, FKBP5 and FKBP4. This study tested the transcriptome changes in NR3C1/GR regulation in response to natural mating and/or cervical deposition of the sperm-peak ejaculate fraction collected using the gloved-hand method (semen or only its seminal plasma), in the preovulatory pig reproductive tract (cervix to infundibulum, 24 h after mating/insemination/infusion treatments). Porcine cDNA microarrays revealed 22 NR3C1-related transcripts, and changes in gene expression were triggered by all treatments, with natural mating showing the largest differences, including NR3C1, FKBP5, FKBP4, hydroxysteroid 11-beta dehydrogenase 1 and 2 (HSD11B1, HSD11B2), and the signal transducer and activator of transcription 5A (STAT5A). Our data suggest that natural mating induces expression changes that might promote a reduction of the cortisol action in the oviductal sperm reservoir. Together with the STAT-mediated downregulation of cytokine immune actions, this reduction may prevent harmful effects by promoting tolerance towards the spermatozoa stored in the oviduct and perhaps elicit spermatozoa activation and detachment after ovulation.

scholarly journals Cofilin 1 Is Revealed as an Inhibitor of Glucocorticoid Receptor by Analysis of Hormone-Resistant Cells

2004 ◽  
Vol 24 (21) ◽  
pp. 9371-9382 ◽  
Author(s):  
Joëlle Rüegg ◽  
Florian Holsboer ◽  
Christoph Turck ◽  
Theo Rein
Keyword(s):  
Glucocorticoid Receptor ◽  
Inhibitory Action ◽  
Hormone Treatment ◽  
Receptor Activity ◽  
Stable Cell Line ◽  
Receptor Interaction ◽  
Two Dimensional Gel Electrophoresis ◽  
Actin Depolymerization ◽  
Glucocorticoid Signaling ◽  
Cytoskeleton Disruption

ABSTRACT Significant knowledge about glucocorticoid signaling has accumulated, yet many aspects remain unknown. We aimed to discover novel factors involved in glucocorticoid receptor regulation that do not necessarily require direct receptor interaction. We achieved this by using a functional genetic screen: a stable cell line which cannot survive hormone treatment was engineered, randomly mutated, and selected in the presence of glucocorticoid. A hormone-resistant clone was analyzed by two-dimensional gel electrophoresis. Differentially expressed proteins were identified and tested as candidates for regulation of the glucocorticoid receptor. An unexpected candidate, cofilin 1, inhibited receptor activity. Cofilin is known to promote actin depolymerization and filament severing. Several experiments suggest that this feature of cofilin is involved in its inhibitory action. Both its actin depolymerization activity and its inhibitory action on the receptor are dependent on its phosphorylation state. Treatment of cells with a cytoskeleton-disrupting agent decreased receptor activity, as did overexpression of actin, particularly a mutant actin that does not polymerize. In addition, overexpression of cofilin and actin as well as chemical cytoskeleton disruption changed the subcellular receptor distribution and upregulated c-Jun, which could constitute the inhibitory mechanism of cofilin. In summary, cofilin represents a novel factor that can cause glucocorticoid resistance.

scholarly journals Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity

2019 ◽  
Author(s):  
Ian Gans ◽  
Ellen I. Hartig ◽  
Shusen Zhu ◽  
Andrea R. Tilden ◽  
Lucie N. Hutchins ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Frameshift Mutation ◽  
Transcriptional Regulator ◽  
Model System ◽  
Dna Binding Domain ◽  
Rna Seq ◽  
Transcriptomic Response ◽  
Glucocorticoid Signaling ◽  
The One

AbstractThe zebrafish has recently emerged as a model system for investigating the developmental roles of glucocorticoid signaling and the mechanisms underlying glucocorticoid-induced developmental programming. To assess the role of the Glucocorticoid Receptor (GR) in such programming, we used CRISPR-Cas9 to produce a new frameshift mutation, GR369-, which eliminates all potential in-frame initiation codons upstream of the DNA binding domain. Using RNA-seq to ask how this mutation affects the larval transcriptome under both normal conditions and with chronic cortisol treatment, we find that GR mediates most of the effects of the treatment, and paradoxically, that the transcriptome of cortisol-treated larvae is more like that of larvae lacking a GR than that of larvae with a GR, suggesting that the cortisol-treated larvae develop GR resistance. The one transcriptional regulator that was both underexpressed in GR369- larvae and consistently overexpressed in cortisol-treated larvae was klf9. We therefore used CRISPR-Cas9-mediated mutation of klf9 and RNA-seq to assess Klf9-dependent gene expression in both normal and cortisol-treated larvae. Our results indicate that Klf9 contributes significantly to the transcriptomic response to chronic cortisol exposure, mediating the upregulation of proinflammatory genes that we reported previously.

scholarly journals Minireview: New Molecular Mediators of Glucocorticoid Receptor Activity in Metabolic Tissues

2014 ◽  
Vol 28 (7) ◽  
pp. 999-1011 ◽  
Author(s):  
Rucha Patel ◽  
Jasmine Williams-Dautovich ◽  
Carolyn L. Cummins
Keyword(s):  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Drug Targets ◽  
Muscle Wasting ◽  
Hormone Receptors ◽  
Specific Level ◽  
Glucocorticoid Signaling ◽  
Unknown Protein ◽  
Glucocorticoid Response ◽  
Molecular Effects

The glucocorticoid receptor (GR) was one of the first nuclear hormone receptors cloned and represents one of the most effective drug targets available today for the treatment of severe inflammation. The physiologic consequences of endogenous or exogenous glucocorticoid excess are well established and include hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting. However, at the molecular and tissue-specific level, there are still many unknown protein mediators of glucocorticoid response and thus, much remains to be uncovered that will help determine whether activation of the GR can be tailored to improve therapeutic efficacy while minimizing unwanted side effects. This review summarizes recent discoveries of tissue-selective modulators of glucocorticoid signaling that are important in mediating the unwanted side effects of therapeutic glucocorticoid use, emphasizing the downstream molecular effects of GR activation in the liver, adipose tissue, muscle, and pancreas.

Generating diversity in glucocorticoid receptor signaling: mechanisms, receptor isoforms, and post-translational modifications

2010 ◽  
Vol 3 (1) ◽  
Author(s):  
Danielle Duma ◽  
John A. Cidlowski
Keyword(s):  
Glucocorticoid Receptor ◽  
Distribution Patterns ◽  
Specific Response ◽  
Post Translational Modifications ◽  
Receptor Isoforms ◽  
Glucocorticoid Signaling ◽  
Transcriptional Regulatory ◽  
Alternative Mrna Splicing ◽  
Acute And Chronic Inflammation

AbstractGlucocorticoids are necessary for life after birth and regulate numerous homeostatic functions in man, including glucose homeostasis, protein catabolism, skeletal growth, respiratory function, inflammation, development, behavior, and apoptosis. In a clinical setting, they are widely used as anti-inflammatory agents to control both acute and chronic inflammation. Unfortunately, owing to their broad range of physiological actions, patients treated with glucocorticoids for long periods of time experience a variety of serious side effects, including metabolic syndrome, bone loss, and psychiatric disorders including depression, mania, and psychosis. Our understanding of how one hormone or drug regulates all of these diverse processes is limited. Recent studies have shown that multiple glucocorticoid receptor isoforms are produced from one gene via combinations of alternative mRNA splicing and alternative translation initiation. These isoforms possess unique tissue distribution patterns and transcriptional regulatory profiles. Owing to variation in the N-terminal and C-terminal length of glucocorticoid receptor isoforms, different post-translational modifications including ubiquitination, phosphorylation, and sumoylation are predicted, contributing to the complexity of glucocorticoid signaling. Furthermore, increasing evidence suggests that unique glucocorticoid receptor isoform compositions within cells could determine the cell-specific response to glucocorticoids. In this review, we will outline the recent advances made in the characterization of the transcriptional activity and the selective regulation of apoptosis by the various glucocorticoid receptor isoforms.

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