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Kendall J. Blumer - One of the best experts on this subject based on the ideXlab platform.
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regulation of renal hemodynamics and function by RGS2
PLOS ONE, 2015Co-Authors: Patrick Oseiowusu, Li Jie, Elizabeth A Owens, Janaina S Reis, Steven J Forrester, Tatsuo Kawai, Satoru Eguchi, Harpreet Singh, Kendall J. BlumerAbstract:Regulator of G protein signaling 2 (RGS2) controls G protein coupled receptor (GPCR) signaling by acting as a GTPase-activating protein for heterotrimeric G proteins. Certain RGS2 gene mutations have been linked to human hypertension. Renal RGS2 deficiency is sufficient to cause hypertension in mice; however, the pathological mechanisms are unknown. Here we determined how the loss of RGS2 affects renal function. We examined renal hemodynamics and tubular function by monitoring renal blood flow (RBF), glomerular filtration rate (GFR), epithelial sodium channel (ENaC) expression and localization, and pressure natriuresis in wild type (WT) and RGS2 null (RGS2-/-) mice. Pressure natriuresis was determined by stepwise increases in renal perfusion pressure (RPP) and blood flow, or by systemic blockade of nitric oxide synthase with L-NG-Nitroarginine methyl ester (L-NAME). Baseline GFR was markedly decreased in RGS2-/- mice compared to WT controls (5.0 ± 0.8 vs. 2.5 ± 0.1 μl/min/g body weight, p<0.01). RBF was reduced (35.4 ± 3.6 vs. 29.1 ± 2.1 μl/min/g body weight, p=0.08) while renal vascular resistance (RVR; 2.1 ± 0.2 vs. 3.0 ± 0.2 mmHg/μl/min/g body weight, p<0.01) was elevated in RGS2-/- compared to WT mice. RGS2 deficiency caused decreased sensitivity and magnitude of changes in RVR and RBF after a step increase in RPP. The acute pressure–natriuresis curve was shifted rightward in RGS2-/- relative to WT mice. Sodium excretion rate following increased RPP by L-NAME was markedly decreased in RGS2-/- mice and accompanied by increased translocation of ENaC to the luminal wall. We conclude that RGS2 deficiency impairs renal function and autoregulation by increasing renal vascular resistance and reducing renal blood flow. These changes impair renal sodium handling by favoring sodium retention. The findings provide a new line of evidence for renal dysfunction as a primary cause of hypertension.
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abstract 640 RGS2 deficiency impairs renal hemodynamics and function
Hypertension, 2014Co-Authors: Patrick Oseiowusu, Kendall J. BlumerAbstract:Regulator of G protein signaling 2 (RGS2) regulates signaling by acting as a GTPase-activating protein for Gq/11α and Gi/oα subunits of heterotrimeric G proteins. Certain single nucleotide polymorphisms and loss-of-function mutations of RGS2 have been linked to human hypertension. RGS2 deficiency in the kidney is sufficient to cause hypertension in mice; however, the renal pathophysiological mechanisms are unknown. Here, we assessed renal hemodynamics and function using renal blood flow (RBF) and glomerular filtration rate (GFR) measurements, and assessment of pressure natriuresis in wild type (WT) and RGS2 null (RGS2-/-) mice. GFR was measured by plasma clearance of FITC-inulin. Pressure natriuresis was determined by increasing renal perfusion pressure (RPP) stepwise by clamping the superior mesenteric and celiac arteries, and abdominal aorta, while total RBF was simultaneously recorded with flow probe. Baseline GFR was markedly decreased in RGS2-/- mice compared to WT controls (1.8 ± 0.1 vs. 1.1 ± 0.1 ml/min/g kidney weight, p=0.004). Renal conductance was reduced (70 ± 9 vs. 51 ± 3 μl/min/g kidney weight, p=0.006) while renal vascular resistance (RVR; 14.9 ± 2.2 vs. 20.2 ± 1.3 mmHg/ml/min/g kidney weight, p=0.002) was elevated in RGS2-/- compared to WT mice. The absence of RGS2 resulted in decreased sensitivity and magnitude of change in RVR (WT: 11.17 ± 1.94 vs. RGS2-/-: 6.87 ± 0.90 mmHg/ml/min/g) and conductance (WT: -25.69 ± 3.22 vs. RGS2-/-: -13.87 ± 2.40 ml/min/mmHg/g) after a step increase in RPP. The acute pressure-natriuresis curve shifted rightward in RGS2-/- relative to WT, with no change in the slope. Fractional sodium excretion was unaffected by RGS2 deficiency. We conclude that RGS2 deficiency impairs renal function and autoregulation by increasing renal vascular resistance and reducing effective renal blood flow. The findings provide a new line of evidence for renal vascular dysfunction as a primary cause of hypertension. Mutations or downregulation of RGS2 in the kidney may contribute to human hypertension by causing renal hypoperfusion and decreased GFR. Signaling pathways regulated by RGS2 may provide therapeutic targets in hypertension patients harboring mutations that potentially decrease expression and/or function of RGS2.
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RGS2 deficient mice exhibit decreased intraocular pressure and increased retinal ganglion cell survival
Molecular Vision, 2009Co-Authors: Miyuki Inouemochita, Kendall J. Blumer, Toshihiro Inoue, David L Epstein, P V RaoAbstract:Purpose: Contractile activity of the trabecular meshwork (TM) and ciliary muscle (CM) influences aqueous humor drainage; however, the mechanisms linking tissue contractility and regulation of aqueous humor drainage are not well understood. Regulator of G Protein Signaling 2 (RGS2), a GTPase-activating protein of the Gαq family of proteins, plays a critical role in regulation of contractile activity of vascular smooth muscle and in blood pressure homeostasis. To explore a potential role for RGS2 in intraocular pressure (IOP) homeostasis, we evaluated RGS2 knockout (RGS2−/−) mice for changes in IOP. Methods: IOP was measured using a rebound tonometer in awake male RGS2 −/− and littermate wild-type mice. Histological and immunofluorescence analyses were performed to evaluate changes in the iridocorneal structure, actomyosin organization in CM and TM, and retinal ganglion cell survival in both central and peripheral retina. Results: In repeated measurements, IOP was found to be consistently lower in the RGS2−/− mice compared to littermate wild-type mice. This change in IOP appears to be associated with increased actin filament assembly in the CM, and widening of the Schlemm’s canal in the aqueous humor drainage pathway. Furthermore, ganglion cell number in the central retina was found to be significantly higher in the RGS2 −/− mice relative to wild-type mice. Conclusions: The data suggest that the deficiency of RGS2 decreased IOP, presumably due to increased aqueous humor drainage in association with increased CM contraction. These data indicate a potentially critical role for RGS2 in homeostasis of IOP and for retinal ganglion cell survival.
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sympathetic nerve traffic and circulating norepinephrine levels in RGS2 deficient mice
Autonomic Neuroscience: Basic and Clinical, 2007Co-Authors: Jens Tank, Kendall J. Blumer, Michael Obst, Andre Diedrich, Robert J Brychta, Karsten Heusser, Jens Jordan, Friedrich C Luft, Volkmar GrossAbstract:Abstract Regulator of G protein signaling 2 (RGS2−/−) deficient mice feature an increased resting blood pressure and an excessive pressor response to stress. We measured renal sympathetic nerve activity (RSNA) directly to test the hypothesis that RSNA is increased in RGS2−/− mice, compared to RGS2+/+ mice. Seventeen mice (RGS2−/−, n = 9; RGS2+/+, n = 8) were anesthetized with isoflurane. We cannulated the left jugular vein for drug administration. Renal sympathetic nerve activity (RSNA) was recorded using bipolar electrodes. Arterial blood pressure (BP) from the femoral artery, ECG (needle electrodes), and RSNA were recorded (sample rate 10 kHz) simultaneously. RSNA was analysed off-line using a modified wavelet de-noising technique and the classical discriminator method. RSNA detected during phenylephrine bolus injections or after the animals death was subtracted from baseline values. Mean arterial blood pressure, norepinephrine plasma levels, the responsiveness to vasoactive drugs, and the sympathetic baroreflex gain were similar in anesthetized RGS2+/+ and RGS2−/− animals. RSNA was lower in RGS2−/− mice compared to wild-type controls (wavelet: spike rate in Hz: RGS2+/+ 25.5 ± 5.1; RGS2−/− 17.4 ± 4.0; discriminator method: RGS2+/+ 41.4 ± 5.7, RGS2−/− 22.0 ± 4.3, p
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regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cgmp dependent protein kinase
Journal of Biological Chemistry, 2007Co-Authors: Patrick Oseiowusu, Ryan M Drenan, Thomas H Steinberg, Kendall J. BlumerAbstract:Abstract RGS2, a GTPase-activating protein (GAP) for Gqα, regulates vascular relaxation and blood pressure. RGS2 can be phosphorylated by type Iα cGMP-dependent protein kinase (cGKIα), increasing its GAP activity. To understand how RGS2 and cGKIα regulate vascular smooth muscle signaling and function, we identified signaling pathways that are controlled by cGMP in an RGS2-dependent manner and discovered new mechanisms whereby cGK activity regulates RGS2. We show that RGS2 regulates vasoconstrictor-stimulated Ca2+ store release, capacitative Ca2+ entry, and noncapacitative Ca2+ entry and that RGS2 is required for cGMP-mediated inhibition of vasoconstrictor-elicited phospholipase Cβ activation, Ca2+ store release, and capacitative Ca2+ entry. RGS2 is degraded in vascular smooth muscle cells via the proteasome. Inhibition of cGK activity blunts RGS2 degradation. However, inactivation of the cGKIα phosphorylation sites in RGS2 does not stabilize the protein, suggesting that cGK activity regulates RGS2 degradation by other mechanisms. cGK activation promotes association of RGS2 with the plasma membrane by a mechanism requiring its cGKIα phosphorylation sites. By regulating GAP activity, plasma membrane association, and degradation, cGKIα therefore may control a cycle of RGS2 activation and inactivation. By diminishing cGK activity, endothelial dysfunction may impair RGS2 activation, thereby blunting vascular relaxation and contributing to hypertension.
Scott P. Heximer - One of the best experts on this subject based on the ideXlab platform.
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a new twist on rgs protein selectivity
Structure, 2013Co-Authors: Scott P. HeximerAbstract:G protein-coupled receptors mediate a wide array of physiologic stimuli and, together with their regulators such as RGS2, are essential components of cellular signaling and function. RGS2 is a selective inhibitor of the Gαq class of α subunits. In this issue of Structure, Nance and colleagues provide structural insight into the features of RGS2 that mediate its potent and selective regulation of Gαq function.
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β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Neil S. Holden, Scott P. Heximer, David P. Siderovski, Matthew J. Bell, Christopher F. Rider, Elizabeth M. King, David D. Gaunt, Richard Leigh, Malcolm Johnson, Mark A. GiembyczAbstract:In asthma and chronic obstructive pulmonary disease, activation of Gq-protein–coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β2-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates Gq signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, RGS2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases.
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Abstract 308: RGS2 Is An Endogenous Inhibitor Of Insulin Signaling
Circulation, 2008Co-Authors: Prem Sharma, Jennie Bever, Scott P. Heximer, Carmen W. Dessauer, Jerrold M. OlefskyAbstract:Background: Insulin resistance is the hallmark of type 2 diabetes and is a known risk factor for the development of cardiovascular diseases. We have determined that overexpression of a GTPase-activating protein, RGS2 decreases insulin sensitivity. This study describes RGS2 regulation of insulin signaling pathways in order to assess whether this information can be used to reverse insulin insensitivity in diabetes. Hypothesis, Methods and Results: RGS2 protein levels were elevated 3 to 5-fold in white adipose tissues from ob/ob and high fat diet induced Insulin Resistant mice. Further, RGS2 protein is elevated in insulin resistant 3T3-L1 adipocytes treated chronically with either insulin, ET-1, or TNF-aplha. Further, SiRNA knockdown of endogenous RGS2 protein increases basal, insulin independent and insulin-dependent GLUT4 translocation. We hypothesized that the RGS2 regulatory system is defective/overactive in insulin resistance, and that a modulation of this regulatory system by RGS2 inhibition would improve insulin sensitivity. Thus, we determined the mechanisms whereby RGS2 modulates insulin sensitivity in 3T3-L1 adipocytes; focusing on insulin-regulated G-protein/PI3-K pathways leading to GLUT4 translocation and glucose uptake; utilizing adenoviruses over-expressing wild-type and mutants RGS2, as well as by siRNA-mediated knock down of endogenous RGS2. We overexpressed the Wild-Type (WT), GTPase defective (GD), and plasma membrane translocation defective (TD) RGS2 proteins in 3T3-L1 adipocytes. Overexpression of WT RGS2 leads to ~ 50% inhibition of insulin induced 2-DOG uptake, without affecting IR Tyr phosphorylation. RGS2 constitutively associates with Galpha/q11, and prevent its Tyr phosphorylation and activation by insulin. Interestingly, insulin-stimulated PKClambda phosphorylation was completely blocked by RGS2, whereas, AKT phosphorylation was minimally inhibited. Neither the insulin receptor tyrosine phosphorylation nor insulin-stimulated MAPK phosphorylation was affected by RGS2. Conclusion: This study identifies a novel role of RGS2 in cellular insulin resistance by negatively regulating signaling through the Galpha/q11 pathway to glucose uptake. This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).
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the RGS2 gene product from a candidate hypertension allele shows decreased plasma membrane association and inhibition of gq
Molecular Pharmacology, 2008Co-Authors: Sam Tirgari, Scott P. HeximerAbstract:Hypertension is a leading risk factor for the development of cardiovascular disease. Data from human and animal studies suggest that RGS2, a potent inhibitor of Gq signaling, is important for blood pressure regulation. Several RGS2 mutations in the Japanese population have been found to be associated with hypertension. The product of one of these alleles, R44H, is mutated within the amino terminal amphipathic α-helix domain, the region responsible for plasma membrane-targeting. The functional consequence of this mutation and its potential link to the development of hypertension, however, are not known. In this study, we showed that R44H was a weaker inhibitor of receptor-mediated Gq signaling than wild-type RGS2. Confocal microscopy revealed that YFP-tagged R44H bound to the plasma membrane less efficiently than wild-type RGS2. R44 is one of the basic residues positioned to stabilize lipid bilayer interaction of the RGS2 amphipathic helix domain. Tryptophan fluorescence and circular dichroism studies of this domain showed that the R44H mutation prevented proper entrenchment of hydrophobic residues into the lipid bilayer without disrupting helix-forming capacity. Together, these data suggest that decreasing the side-chain length and flexibility at R44 prevented proper lipid bilayer association and function of RGS2. Finally, the R44H protein did not behave as a dominant-negative interfering mutant. Thus, our data are consistent with the notion that a R44H missense mutation in human RGS2 produces a hypomorphic allele that may lead to altered receptor-mediated Gq inhibition and contribute to the development of hypertension in affected subjects.
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unique hydrophobic extension of the RGS2 amphipathic helix domain imparts increased plasma membrane binding and function relative to other rgs r4 b subfamily members
Journal of Biological Chemistry, 2007Co-Authors: Suneela Ramineni, John R Hepler, David M Thal, R Natesh, John J G Tesmer, Scott P. HeximerAbstract:RGS2 and RGS5 are inhibitors of G-protein signaling belonging to the R4/B subfamily of RGS proteins. We here show that RGS2 is a much more potent attenuator of M1 muscarinic receptor signaling than RGS5. We hypothesize that this difference is mediated by variation in their ability to constitutively associate with the plasma membrane (PM). Compared with full-length RGS2, the RGS-box domains of RGS2 and RGS5 both show reduced PM association and activity. Prenylation of both RGS-box domains increases activity to RGS2 levels, demonstrating that lipid bilayer targeting increases RGS domain function. Amino-terminal domain swaps confirm that key determinants of localization and function are found within this important regulatory domain. An RGS2 amphipathic helix domain mutant deficient for phospholipid binding (L45D) shows reduced PM association and activity despite normal binding to the M1 muscarinic receptor third intracellular loop and activated Galpha(q). Replacement of a unique dileucine motif adjacent to the RGS2 helix with corresponding RGS5 residues disrupts both PM localization and function. These data suggest that RGS2 contains a hydrophobic extension of its helical domain that imparts high efficiency binding to the inner leaflet of the lipid bilayer. In support of this model, disruption of membrane phospholipid composition with N-ethylmaleimide reduces PM association of RGS2, without affecting localization of the M1 receptor or Galpha(q). Together, these data indicate that novel features within the RGS2 amphipathic alpha helix facilitate constitutive PM targeting and more efficient inhibition of M1 muscarinic receptor signaling than RGS5 and other members of the R4/B subfamily.
Peter Chidiac - One of the best experts on this subject based on the ideXlab platform.
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RGS2 is a component of the cellular stress response
Biochemical and Biophysical Research Communications, 2012Co-Authors: Chau H Nguyen, Peishen Zhao, Alina J Sobiesiak, Peter ChidiacAbstract:Regulator of G protein signaling (RGS) proteins are GTPase accelerating proteins for heterotrimeric G protein α-subunits. RGS2 has recently been shown to have additional G protein-independent functions including control of ion channel currents, microtubule polymerization, and protein synthesis. Cellular levels of RGS2 mRNA and protein are upregulated in response to various forms of stress suggesting that it may be a stress-adaptive protein; however, direct evidence to support this notion has remained elusive. In this report, we show that thermal stress upregulates RGS2 expression and this serves to arrest de novo protein synthesis. The latter is an established cellular response to stress. Inhibiting the stress-induced RGS2 upregulation by way of siRNA knockdown diminished the repression of global protein synthesis. The collective results of our study implicate RGS2 upregulation as a cellular mechanism of controlling de novo protein synthesis in response to stress. This work provides greater insight into the stress proteome and the role of RGS2.
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resistance to age related normal body weight gain in RGS2 deficient mice
Cellular Signalling, 2011Co-Authors: Caroline Nunn, Minxu Zou, Peishen Zhao, Kelly M Summers, Christopher G Guglielmo, Peter ChidiacAbstract:Abstract RGS2 (regulator of G protein signaling 2) is known to limit signals mediated via Gq- and Gs-coupled GPCRs (G protein coupled receptors), and it has been implicated in the differentiation of several cells types. The physiology of RGS2 knockout mice ( RGS2 −/− ) has been studied in some detail, however, a metabolic phenotype has not previously been reported. We observed that old (21–24 month) RGS2 −/− mice weigh much less than wild-type C57BL/6 controls, and exhibit greatly reduced fat deposits, decreased serum lipids, and low leptin levels. Lower weight was evident as early as four weeks and continued throughout life. Younger adult male RGS2 −/− mice (4–8 months) were found to show similar strain-related differences as the aged animals, as well improved glucose clearance and insulin sensitivity, and enhanced beta-adrenergic and glucagon signaling in isolated hepatocytes. In addition, RGS2 −/− pre-adipocytes had reduced levels of differentiation markers (Peroxisome proliferator-activated receptor γ (PPARγ); lipoprotein lipase (Lpl); CCAAT/enhancer binding protein α (CEBPα)) and also RGS2 −/− white adipocytes were small relative to controls, suggesting altered adipogenesis. In wild-type animals, RGS2 mRNA was decreased in brown adipose tissue after cold exposure (7 h at 4 °C) but increased in white adipose tissue in response to a high fat diet, also suggesting a role in lipid storage. No differences between strains were detected with respect to food intake, energy expenditure, GPCR-stimulated lipolysis, or adaptive thermogenesis. In conclusion this study points to RGS2 as being an important regulatory factor in controlling body weight and adipose function.
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RGS2 inhibits beta adrenergic receptor induced cardiomyocyte hypertrophy
Cellular Signalling, 2010Co-Authors: Caroline Nunn, Anju A Roy, Minxu Zou, Lorrie A Kirshenbaum, Alina J Sobiesiak, Peter ChidiacAbstract:The chronic stimulation of certain G protein-coupled receptors promotes cardiomyocyte hypertrophy and thus plays a pivotal role in the development of human heart failure. The beta-adrenergic receptors (beta-AR) are unique among these in that they signal via Gs, whereas others, such as the alpha1-adrenergic (alpha1-AR) and endothelin-1 (ET-1) receptors, predominantly act through Gq. In this study, we investigated the potential role of regulator of G protein signalling 2 (RGS2) in modulating the hypertrophic effects of the beta-AR agonist isoproterenol (ISO) in rat neonatal ventricular cardiomyocytes. We found that ISO-induced hypertrophy in rat neonatal ventricular myocytes was accompanied by the selective upregulation of RGS2 mRNA, with little or no change in RGS1, RGS3, RGS4 or RGS5. The adenylyl cyclase activator forskolin had a similar effect suggesting that it was mediated through cAMP production. To study the role of RGS2 upregulation in beta-AR-dependent hypertrophy, cardiomyocytes were infected with adenovirus encoding RGS2 and assayed for cell growth, markers of hypertrophy, and beta-AR signalling. ISO-induced increases in cell surface area were virtually eliminated by the overexpression of RGS2, as were increases in alpha-skeletal actin and atrial natriuretic peptide. RGS2 overexpression also significantly attenuated ISO-induced extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Akt activation, which may account for, or contribute to, its observed antihypertrophic effects. In contrast, RGS2 overexpression significantly activated JNK MAP kinase, while decreasing the potency but not the maximal effect of ISO on cAMP accumulation. In conclusion, the present results suggest that RGS2 negatively regulates hypertrophy induced by beta-AR activation and thus may play a protective role in cardiac hypertrophy.
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translational control by RGS2
Journal of Cell Biology, 2009Co-Authors: Chau Hoang Nguyen, Hong Ming, Peishen Zhao, Lynne Hugendubler, Robert Gros, Scot R Kimball, Peter ChidiacAbstract:The regulator of G protein signaling (RGS) proteins are a family of guanosine triphosphatase (GTPase)–accelerating proteins. We have discovered a novel function for RGS2 in the control of protein synthesis. RGS2 was found to bind to eIF2Bϵ (eukaryotic initiation factor 2B ϵ subunit) and inhibit the translation of messenger RNA (mRNA) into new protein. This effect was not observed for other RGS proteins tested. This novel function of RGS2 is distinct from its ability to regulate G protein–mediated signals and maps to a stretch of 37 amino acid residues within its conserved RGS domain. Moreover, RGS2 was capable of interfering with the eIF2–eIF2B GTPase cycle, which is a requisite step for the initiation of mRNA translation. Collectively, this study has identified a novel role for RGS2 in the control of protein synthesis that is independent of its established RGS domain function.
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hippocampal long term potentiation is enhanced in urethane anesthetized RGS2 knockout mice
Hippocampus, 2009Co-Authors: Matthew R Hutchison, Peter Chidiac, Stan L LeungAbstract:RGS2 is a member of the regulator of G-protein signaling (RGS) family and has been implicated in cellular mechanisms associated with neuronal plasticity. Long-term potentiation (LTP) of RGS2 knockout and wild-type mice was examined at the Schaffer collaterals to CA1 pathway in urethane-anesthetized mice in vivo to examine RGS2's possible role in the regulation of potentiation. As compared to wild-type mice, RGS2 knockouts demonstrated much stronger LTP of the extracellular population spikes at the somatic and dendritic layers in CA1 region and more pronounced LTP of the population excitatory postsynaptic current sink. Under baseline conditions, RGS2 knockouts showed lower paired-pulse facilitation of the excitatory postsynaptic potentials and associated current sinks in vivo as compared with wild-type mice. The data show for the first time that RGS2 deficient mice in vivo differ from wild-type mice in both short-term and long-term synaptic plasticity suggesting that RGS2 serves as a negative regulator of long-term synaptic plasticity. © 2009 Wiley-Liss, Inc.
M-f Lin - One of the best experts on this subject based on the ideXlab platform.
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Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells
Oncogene, 2006Co-Authors: X Cao, J Qin, Y Xie, O Khan, F Dowd, M Scofield, M-f LinAbstract:Hormones acting through G protein-coupled receptors (GPCRs) can cause androgen-independent activation of androgen receptor (AR) in prostate cancer cells. Regulators of G-protein signaling (RGS) proteins, through their GTPase activating protein (GAP) activities, inhibit GPCR-mediated signaling by inactivating G proteins. Here, we identified RGS2 as a gene specifically downregulated in androgen-independent prostate cancer cells. Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgen-independent LNCaP cells and CWR22Rv1 cells. In LNCaP cells, RGS2 inhibited G_q-coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated G_qQ209L mutant whereas silencing endogenous RGS2 by siRNA enhanced G_qQ209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive G_qQ209L/G188S-induced AR activation. Furthermore, extracellular signal-regulated kinase 1/2 (ERK1/2) was found to be involved in RGS2-mediated regulation of androgen-independent AR activity. In addition, RGS2 functioned as a growth suppressor for androgen-independent LNCaP cells whereas androgen-sensitive LNCaP cells with RGS2 silencing had a growth advantage under steroid-reduced conditions. Finally, RGS2 expression level was significantly decreased in human prostate tumor specimens. Taken together, our results suggest RGS2 as a novel regulator of AR signaling and its repression may be an important step during prostate tumorigenesis and progression.
Jacques G Lussier - One of the best experts on this subject based on the ideXlab platform.
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expression and regulation of regulator of g protein signaling protein 2 RGS2 in equine and bovine follicles prior to ovulation molecular characterization of RGS2 transactivation in bovine granulosa cells
Biology of Reproduction, 2014Co-Authors: Khampoun Sayasith, Jean Sirois, Jacques G LussierAbstract:ABSTRACT The luteinizing hormone preovulatory surge stimulates several signal pathways essential for ovulation, and the regulator of G-protein signaling protein-2 (RGS2) is thought to be involved in this process. The objectives of this study were to characterize the regulation of RGS2 transcripts in equine and bovine follicles prior to ovulation and to determine its transcriptional control in bovine granulosa cells. To assess the regulation of equine RGS2 prior to ovulation, RT-PCR was performed using total RNA extracted from equine follicles collected at various times after human chorionic gonadotropin (hCG) injection. Results showed that RGS2 mRNA levels were very low at 0 h but markedly increased 12–39 h post-hCG (P < 0.05). In the bovine species, results revealed that RGS2 mRNA levels were low in small and dominant follicles and in ovulatory follicles obtained at 0 h, but markedly increased in ovulatory follicles 6–24 h post-hCG (P < 0.05). To study the molecular control of RGS2 expression, primary cu...
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expression and regulation of regulator of g protein signaling protein 2 RGS2 in equine and bovine follicles prior to ovulation molecular characterization of RGS2 transactivation in bovine granulosa cells
Biology of Reproduction, 2014Co-Authors: Khampoun Sayasith, Jean Sirois, Jacques G LussierAbstract:The luteinizing hormone preovulatory surge stimulates several signal pathways essential for ovulation, and the regulator of G-protein signaling protein-2 (RGS2) is thought to be involved in this process. The objectives of this study were to characterize the regulation of RGS2 transcripts in equine and bovine follicles prior to ovulation and to determine its transcriptional control in bovine granulosa cells. To assess the regulation of equine RGS2 prior to ovulation, RT-PCR was performed using total RNA extracted from equine follicles collected at various times after human chorionic gonadotropin (hCG) injection. Results showed that RGS2 mRNA levels were very low at 0 h but markedly increased 12-39 h post-hCG (P < 0.05). In the bovine species, results revealed that RGS2 mRNA levels were low in small and dominant follicles and in ovulatory follicles obtained at 0 h, but markedly increased in ovulatory follicles 6-24 h post-hCG (P < 0.05). To study the molecular control of RGS2 expression, primary cultures of bovine granulosa cells were used. Stimulation with forskolin induced an up-regulation of RGS2 mRNA in vitro. Studies using 5'-deletion mutants identified a minimal region containing full-length basal and forskolin-inducible RGS2 promoter activities. Site-directed mutagenesis indicated that these activities were dependent on CRE and ETS1 cis-elements. Electrophoretic mobility shift assays confirmed the involvement of these elements and revealed their interactions with CREB1 and ETS1 proteins. Chromatin immunoprecipitation assays confirmed endogenous interactions of these proteins with the RGS2 promoter in granulosa cells. Forskolin-inducible RGS2 promoter activity and mRNA expression were markedly decreased by PKA and ERK1/2 inhibitors, and treatment with an antagonist of PGR (RU486) and inhibitors of PTGS2 (NS398) and EGFR (PD153035) blocked the forskolin-dependent RGS2 transcript expression, suggesting the importance of RGS2 in ovulation. Collectively, this study reports for the first time the gonadotropin-dependent up-regulation of RGS2 in equine and bovine preovulatory follicles and presents some of the regulatory controls involved in RGS2 gene expression in granulosa cells.
