Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA127193 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:affy_fsh_human - affy_fsh_human - - G protein-coupled receptors (GPCR) are centrally involved in most physiological processes and are a major drug targets. They transduce extracellular signals inside the cells through at least two different mechanisms: i) the classical coupling to heterotrimeric G proteins and ii) a newly discovered beta-arrestin-dependent pathway. The fundamental issue of the respective impacts that these two transduction mechanisms exert on gene regulation has not been clearly addressed to date. To tackle this question, we have developed two mutants of the follicle stimulating hormone (FSH) receptors which do not couple to G proteins upon FSH activation but continue to recruit beta-arrestins and signal through them.-In the present study, we compare the wild-type FSH receptor to either the R466A or the T469F mutants. These two mutations are localized in the second intra cellular loop of the FSH receptor and prevent G protein coupling to the active FSH receptor. Each receptor was permanently expressed in HEK-293 cells at comparable levels. Cells were treated or not for 6 hours with 3 nM FSH. Keywords: treated vs untreated comparison,wt vs mutant comparison 18 arrays - Human GenomeU133A 2.0
2011-11-25 | E-GEOD-21982 | biostudies-arrayexpress
Project description:affy_fsh_human - affy_fsh_human - - G protein-coupled receptors (GPCR) are centrally involved in most physiological processes and are a major drug targets. They transduce extracellular signals inside the cells through at least two different mechanisms: i) the classical coupling to heterotrimeric G proteins and ii) a newly discovered beta-arrestin-dependent pathway. The fundamental issue of the respective impacts that these two transduction mechanisms exert on gene regulation has not been clearly addressed to date. To tackle this question, we have developed two mutants of the follicle stimulating hormone (FSH) receptors which do not couple to G proteins upon FSH activation but continue to recruit beta-arrestins and signal through them.-In the present study, we compare the wild-type FSH receptor to either the R466A or the T469F mutants. These two mutations are localized in the second intra cellular loop of the FSH receptor and prevent G protein coupling to the active FSH receptor. Each receptor was permanently expressed in HEK-293 cells at comparable levels. Cells were treated or not for 6 hours with 3 nM FSH. Keywords: treated vs untreated comparison,wt vs mutant comparison
2011-11-25 | GSE21982 | GEO
Project description:This model is from the article:
Competing G protein-coupled receptor kinases balance G protein and β-arrestin signaling
Heitzler D, Durand G, Gallay N, Rizk A, Ahn S, Kim J, Violin JD, Dupuy L, Gauthier C, Piketty V, Crépieux P, Poupon A, Clément F, Fages F, Lefkowitz RJ, Reiter E. Mol Syst Biol.
2012; 8: 590. 22735336
,
Abstract:
Seven-transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β-arrestins, whose recruitment to the activated receptor is regulated by G protein-coupled receptor kinases (GRKs). In this paper, we combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing extracellular signal-regulated kinase (ERK) activation by the angiotensin II type 1A receptor (AT(1A)R) in human embryonic kidney (HEK)293 cells. We built an abstracted ordinary differential equations (ODE)-based model that captured the available knowledge and experimental data. We inferred the unknown parameters by simultaneously fitting experimental data generated in both control and perturbed conditions. We demonstrate that, in addition to its well-established function in the desensitization of G-protein activation, GRK2 exerts a strong negative effect on β-arrestin-dependent signaling through its competition with GRK5 and 6 for receptor phosphorylation. Importantly, we experimentally confirmed the validity of this novel GRK2-dependent mechanism in both primary vascular smooth muscle cells naturally expressing the AT(1A)R, and HEK293 cells expressing other 7TMRs.
2024-09-02 | BIOMD0000000842 | BioModels
Project description:Nathaniel L. Coggins, Danielle Trakimas, S. Laura Chang, Anna Ehrlich, Paramita Ray, Kathryn E. Luker, Jennifer J. Linderman & Gary D. Luker. CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE 9, 6 (2014).
Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein β-arrestin 2. Differences in CXCL12-dependent recruitment of β-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of β-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with β-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with β-arrestin 2 and exhibit more gradual, prolonged recruitment of β-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with β-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of β-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of β-arrestin 2 to CXCR7. In silico experiments also identified β-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the "competition" with CXCR4 for CXCL12 and recruitment of β-arrestin 2. These results reveal how competition for β-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.
2024-09-02 | BIOMD0000000599 | BioModels
Project description:The multifunctional scaffolding protein β-arrestin-1 plays a vital role in mediating the proliferative effects of nicotine through nAChR signaling. β-arrestins were initially known as negative regulators of GPCR mediated signaling as they promote internalization and desensitization of GPCRs. However, new roles of β-arrestins in receptor trafficking and signaling have been discovered in recent years. They are known to regulate signaling through a number of receptors such as Notch, endothelin A receptor, frizzled, smoothened and the nicotinic cholinergic receptors. Studies from our lab revealed that nAChR signaling induces the translocation of β-arrestin-1 to the nucleus, in a Src dependent manner, where it directly binds to the proliferative E2Fs. Furthermore, the nuclear translocation of β-arrestin-1 results in recruitment of p300 to E2F1 regulated proliferative promoters facilitating histone acetylation and transcription of these promoters. Given the role of β-arrestin-1 in nicotine induced gene expression, we attempted to explore the global association of β-arrestin-1 to the genomic regions upon nicotine stimulation by ChIP sequencing. It was found that β-arrestin-1 is recruited on the promoters of many genes that regulate EMT as well as other regulatory pathways. In this assay, β-arrestin-1 was found to be associated with the promoter regions of genes such as ZNF768, ZNF131, CSF3R, HMGA2, TAL1, RCC1, NKX2-4 etc in response to nicotine stimulation.
2013-12-16 | GSE40689 | GEO
Project description:While much is known about glucose metabolism in yeast, less is known about the receptors and signaling pathways that indicate glucose availability. We obtained metabolic profiles for wildtype and 16 mutants affecting the yeast glucose sensing pathway, comparing 0.05% glucose vs 10 min after glucose addition to 2%. First, we determined that the G protein-coupled receptor (Gpr1/Gpa2) directs early events in glucose utilization while the transceptors (Snf3/Rgt2) regulate subsequent processes and downstream products of glucose metabolism. Whereas the large G protein transmits the signal from its cognate receptor, Ras2 (but not Ras1) integrates responses from both receptor pathways. Second, we determined the relative contributions of the G protein α (Gpa2) and β (Asc1) subunits to glucose-initiated processes. We determined that Gpa2 is primarily involved in regulating carbohydrate metabolism while Asc1 is primarily involved in amino acid metabolism. Both proteins are involved in regulating purine metabolism. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast.
2021-05-10 | ST001786 | MetabolomicsWorkbench
Project description:Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that β-arrestin 2 also promotes virus-induced production of IFN-β and clearance of viruses in macrophages. β-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstreatm stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of β-arrestin 2 at Lys171 facilitates the activation of the cGAS–STING signaling and the production of IFN-β. In vitro, viral infection induces the degradation of β-arrestin 2 to facilitate immune evasion, while a β-blocker, carvedilol, rescues β-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of β-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.
2020-10-22 | GSE159735 | GEO
Project description:The gonadotropin-dependent phase of ovarian folliculogenesis primarily requires follicle-stimulating hormone (FSH) to support one or multiple early antral follicles, dependent on the species, to mature fully and support steroidogenesis, oogenesis, and ovulation, which critically sustain female reproductive cycles and fertility. At molecular levels, FSH binds to its membrane receptor, FSHR, in granulosa cells to activate a suite of genes and signal transduction pathways. Both insufficient FSH caused by genetic or non-genetic reasons and excessive FSH used for ovarian stimulation in assisted reproductive technology (ART) can cause poor female reproductive outcomes, but the underlying mechanisms remain elusive. Here, we used an ex vivo folliculogenesis and oogenesis system along with single-follicle and -oocyte RNA sequencing analysis and other approaches to investigate the effects of different concentrations of FSH on key follicular events. The results revealed that a minimum FSH threshold is required for follicle maturation, and such threshold is moderately variable among individual follicles. FSH at the subthreshold, threshold, and suprathreshold levels induced distinct expression patterns of follicle maturation-related genes and the entire follicular transcriptomics. The RNA-seq analysis identified several new genes and signaling pathways that may critically regulate follicle maturation. The treatment of excessive FSH resulted in multiple ovarian disorders including premature luteinization, high production of androgen and proinflammatory factors, and reduced expression of energy metabolism-related genes in oocytes. Together, our study enables a better understanding of the gonadotropin-dependent folliculogenesis, and the novel findings shed crucial insights into how ovarian stimulation with high doses of FSH used in ART impact follicular health, oocyte quality, pregnancy success, and systemic health.
2024-06-05 | GSE249196 | GEO
Project description:Activation of ERK1 and ERK2 is essential in regulation of a wide variety of cellular and physiological processes. In native inner medullary collecting ducts, vasopressin (AVP) working through the V2 subtype vasopressin receptor (V2R)-mediated activation of Gαs, inhibits ERK1 and ERK2 activity. However, it has been reported that V2R can signal independently of Gαs through the activation of β-arrestin, which activates ERK1 and ERK2. Vaptans, V2R antagonists that function as so-called “inverse agonists”, have the potential of promoting cell proliferation via β-arrestin-dependent ERK activation. Here we use the mpkCCD cell line which natively expresses V2R to investigate the effects of AVP, the V2-selective analog dDAVP, and tolvaptan on ERK1 and ERK2 phosphorylation and activation. We demonstrated that ERK1 and ERK2 phosphorylation in mpkCCD cells was significantly reduced by either AVP or dDAVP, in contrast to the increases seen in non-collecting duct cells overexpressing V2R. We also found that tolvaptan has a strong effect to increase ERK1 and ERK2 phosphorylation in the presence of dDAVP and that the tolvaptan effect to increase ERK1 and ERK2 phosphorylation is absent in PKA-null mpkCCD cells. Thus, it appears that the tolvaptan effect to increase ERK activation is PKA-dependent and, therefore, not mediated by the β-arrestin pathway. Overall, the studies show that AVP decreases and that tolvaptan increases ERK1 and ERK2 activation in cells expressing V2R at endogenous levels, and provide no evidence for a role for β-arrestin in the regulation of ERK1 and ERK2 activity.
2024-09-22 | GSE235936 | GEO
Project description:Activation of ERK1 and ERK2 is essential in regulation of a wide variety of cellular and physiological processes. In native inner medullary collecting ducts, vasopressin (AVP) working through the V2 subtype vasopressin receptor (V2R)-mediated activation of Gαs, inhibits ERK1 and ERK2 activity. However, it has been reported that V2R can signal independently of Gαs through the activation of β-arrestin, which activates ERK1 and ERK2. Vaptans, V2R antagonists that function as so-called “inverse agonists”, have the potential of promoting cell proliferation via β-arrestin-dependent ERK activation. Here we use the mpkCCD cell line which natively expresses V2R to investigate the effects of AVP, the V2-selective analog dDAVP, and tolvaptan on ERK1 and ERK2 phosphorylation and activation. We demonstrated that ERK1 and ERK2 phosphorylation in mpkCCD cells was significantly reduced by either AVP or dDAVP, in contrast to the increases seen in non-collecting duct cells overexpressing V2R. We also found that tolvaptan has a strong effect to increase ERK1 and ERK2 phosphorylation in the presence of dDAVP and that the tolvaptan effect to increase ERK1 and ERK2 phosphorylation is absent in PKA-null mpkCCD cells. Thus, it appears that the tolvaptan effect to increase ERK activation is PKA-dependent and, therefore, not mediated by the β-arrestin pathway. Overall, the studies show that AVP decreases and that tolvaptan increases ERK1 and ERK2 activation in cells expressing V2R at endogenous levels, and provide no evidence for a role for β-arrestin in the regulation of ERK1 and ERK2 activity.
2023-11-17 | GSE243773 | GEO