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A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.

ABSTRACT: G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the G? subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the G? subunit, a reaction catalyzed by RGS proteins. Using yeast as a tool to study GPCR signaling in isolation, we define an interaction between the cognate GPCR (Mam2) and RGS (Rgs1), mapping the interaction domains. This reaction tethers Rgs1 at the plasma membrane and is essential for physiological signaling response. In vivo quantitative data inform the development of a kinetic model of the GTPase cycle, which extends previous attempts by including GPCR-RGS interactions. In vivo and in silico data confirm that GPCR-RGS interactions can impose an additional layer of regulation through mediating RGS subcellular localization to compartmentalize RGS activity within a cell, thus highlighting their importance as potential targets to modulate GPCR signaling pathways.

SUBMITTER: Croft W

PROVIDER: S-EPMC3779728 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.

Croft Wayne W Hill Claire C McCann Eilish E Bond Michael M Esparza-Franco Manuel M Bennett Jeannette J Rand David D Davey John J Ladds Graham G

The Journal of biological chemistry 20130730 38

G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the Gα subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the Gα subunit, a reaction catalyzed by RGS proteins. Using yeas ...[more]

PMID: 23900842

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Project description:BackgroundAlterations in the regulator of G-protein signaling (RGS) pathway have been implicated in several cancers; therefore, the authors investigated the role of such alterations in overall bladder cancer risk, recurrence, progression, and survival.MethodsIn this case-control series, 803 patients with bladder cancer were frequency-matched with a control cohort of 803 healthy individuals. Ninety-five single-nucleotide polymorphisms (SNPs) in 17 RGS genes were investigated for an association with overall bladder cancer risk, recurrence, and progression in patients who had nonmuscle-invasive bladder cancer (NMIBC) and for an association with death in patients who had muscle-invasive bladder cancer (MIBC). Cumulative effects and classification and regression tree analyses were performed for SNPs that were associated with overall bladder cancer risk. Kaplan-Meier plots were created to evaluate differences in the survival of patients with MIBC.ResultsReference SNP 10759 (rs10759) on the RGS4 gene demonstrated the greatest association with overall bladder cancer risk, conferring a 0.77-fold reduced risk with an increasing number of variant alleles (P < .001). A cumulative effects analysis that included all 5 significant SNPs demonstrated an increasing risk with the number of unfavorable genotypes (odds ratio, 4.13; 95% confidence interval, 2.14-7.98). In patients with NMIBC, 11 SNPs were identified that had an association with disease recurrence, and 13 SNPs were associated with disease progression. Of the 10 SNPs that were associated with death in patients with MIBC, rs2344673 in an additive model was the most significant and was associated with a decreased median survival of 13.3 months compared with 81.9 months in individuals without a variant allele.ConclusionsGenetic variations in the RGS pathway were associated with the overall risk of bladder cancer, recurrence, and progression in patients with NMIBC and with the risk of death in patients with MIBC.

Project description:Croft2013 - GPCR-RGS interaction that compartmentalizes RGS activity Through modelling studies, the classic quaternary complex (ligand-GPCR-G-RGS) has been extended to include an additional layer of regulation through GPCR-RGS interactions, which facilitate the compartmentalization of RGS activity into the plasma membrane and non-plasma compartments. This model is described in the article: A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity. Croft W, Hill C, McCann E, Bond M, Esparza-Franco M, Bennett J, Rand D, Davey J, Ladds G. J Biol Chem. 2013 Sep 20;288(38):27327-42. Abstract: G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the Gα subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the Gα subunit, a reaction catalyzed by RGS proteins. Using yeast as a tool to study GPCR signaling in isolation, we define an interaction between the cognate GPCR (Mam2) and RGS (Rgs1), mapping the interaction domains. This reaction tethers Rgs1 at the plasma membrane and is essential for physiological signaling response. In vivo quantitative data inform the development of a kinetic model of the GTPase cycle, which extends previous attempts by including GPCR-RGS interactions. In vivo and in silico data confirm that GPCR-RGS interactions can impose an additional layer of regulation through mediating RGS subcellular localization to compartmentalize RGS activity within a cell, thus highlighting their importance as potential targets to modulate GPCR signaling pathways. Author's comment on reproducing the plots: To reproduce dose-response plots in the publication, the model is simulated with 12 different ligand concentrations (see parameter Ligand_conc). For each ligand concentration, a single value corresponding to total amount of output must be obtained, by calculating the area under the curve of the trajectory of species z3, from time=0 to time=30. These total output values are then used to build a dose-response plot (authors used GraphPad Prism). Mutant strains are simulated with alternative parameter values or initial conditions specified in the Supplementary Material. This model is hosted on BioModels Database and identified by: BIOMD0000000479 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:G-Protein coupled receptors (GPCRs) activate intracellular signalling pathways by coupling to heterotrimeric G-proteins that control many physiological processes including blood pressure homeostasis. The Regulator of G-Protein Signalling-1 (RGS1) controls the magnitude and duration of downstream GPCR signalling by acting as a GTPase-activating protein for specific G?-proteins. RGS1 has contrasting roles in haematopoietic and non-haematopoietic cells. Rgs1-/-ApoE-/- mice are protected from Angiotensin II (Ang II)-induced aortic aneurysm rupture. Conversely, Ang II treatment increases systolic blood pressure to a greater extent in Rgs1-/-ApoE-/- mice than ApoE-/- mice, independent of its role in myeloid cells. However the precise role of RGS1 in hypertension and vascular-derived cells remains unknown. We determined the effects of Rgs1 deletion on vascular function in ApoE-/- mice. Rgs1 deletion led to enhanced vasoconstriction in aortas and mesenteric arteries from ApoE-/- mice in response to phenylephrine (PE) and U46619 respectively. Rgs1 was shown to have a role in the vasculature, with endothelium-dependent vasodilation being impaired, and endothelium-independent dilatation to SNP being enhanced in Rgs1-/-ApoE-/- mesenteric arteries. To address the downstream signalling pathways in vascular smooth muscle cells (VSMCs) in response to Ang II-stimulation, we assessed pErk1/2, pJNK and pp38 MAPK activation in VSMCs transiently transfected with Rgs1. pErk1/2 signalling but not pJNK and pp38 signalling was impaired in the presence of Rgs1. Furthermore, we demonstrated that the enhanced contractile response to PE in Rgs1-/-ApoE-/- aortas was reduced by a MAPK/Erk (MEK) inhibitor and an L-type voltage gated calcium channel antagonist, suggesting that Erk1/2 signalling and calcium influx are major effectors of Rgs1-mediated vascular contractile responses, respectively. These findings indicate RGS1 is a novel regulator of blood pressure homeostasis and highlight RGS1-controlled signalling pathways in the vasculature that may be new drug development targets for hypertension.

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A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.

Publications

A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.

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