Regulators of G-protein signalling: multifunctional proteins with impact on signalling in the cardiovascular system

Wieland, Thomas; Mittmann, Clemens

doi:10.1016/s0163-7258(02)00326-1

Cited by 120 publications

(101 citation statements)

References 192 publications

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“…RGS proteins play important roles in the regulation of G protein-coupled receptor signaling by binding to the active G subunits and stimulating GTP hydrolysis, thus switching off G protein signaling (31). Both RGS4 and RGS5 have been reported to be negative regulators of AngII signaling through the AT1 receptor (32,33), suggesting that AngII can enhance its own signaling by down-regulating RGS4 and RGS5.…”

Section: Discussionmentioning

confidence: 99%

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Takata

Liu

Yin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

198

181

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Activation of the nuclear hormone receptor peroxisome proliferatoractivated receptor ␦ (PPAR␦) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPAR␦ activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPAR␦ agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPAR␦ activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPAR␦ activation to inhibit AngII signaling, which is atheroprotective.peroxisome proliferator-activated receptor ␦ ͉ vascular inflammation ͉ macrophage

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Section: Discussionmentioning

confidence: 99%

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Takata

Liu

Yin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

198

181

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“…A novel aspect of the modified model ( figure 1d(ii)) in the present study is that we have incorporated the concept of regulation of G-protein signalling (RGS). RGS proteins regulate G-protein signalling by accelerating GTP hydrolysis, and they may be involved in the development of certain cardiovascular pathologies (Wieland & Mittmann 2003;Semplicini et al 2006;Wieland et al 2007;Hendriks-Balk et al 2008). Modulation of GTP hydrolysis by RGS proteins also underlies a voltage-and time-dependent character of the K ACh current in atrial myocytes known as 'relaxation' (figure 3b; Inanobe et al 2001;Ishii et al 2001Ishii et al , 2002.…”

Section: (B) the G-protein Cycle Modelmentioning

confidence: 99%

Cellular modelling: experiments and simulation to develop a physiological model of G-protein control of muscarinic K ⁺ channels in mammalian atrial cells

Murakami

Suzuki

Ishii

et al. 2010

Phil. Trans. R. Soc. A.

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The first model of G-protein-K ACh channel interaction was developed 14 years ago and then expanded to include both the receptor-G-protein cycle and G-protein-K ACh channel interaction. The G-protein-K ACh channel interaction used the Monod-WymanChangeux allosteric model with the idea that one K ACh channel is composed of four subunits, each of which binds one active G-protein subunit (G bg ). The receptor-G-protein cycle used a previous model to account for the steady-state relationship between K ACh current and intracellular guanosine-5-triphosphate at various extracellular concentrations of acetylcholine (ACh). However, simulations of the activation and deactivation of K ACh current upon ACh application or removal were much slower than experimental results. This clearly indicates some essential elements were absent from the model. We recently found that regulators of G-protein signalling are involved in the control of K ACh channel activity. They are responsible for the voltage-dependent relaxation behaviour of K ACh channels. Based on this finding, we have improved the receptor-G-protein cycle model to reproduce the relaxation behaviour. With this modification, the activation and deactivation of K ACh current in the model are much faster and now fall within physiological ranges.

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“…Relatively late identified players in signal transduction via heterotrimeric G proteins are a family of RGS proteins, an acronym for 'regulators of G protein signalling' (excellently reviewed by Wieland and Mittmann 2003). More than 20 different RGS proteins have been identified in humans, all of which stimulate the hydrolysis of GTP of the GTPbound (i.e., activated) Gα subunits and thus accelerate G protein deactivation (Figs.…”

Section: Genetic Variants Of the Regulator Of G Protein Signalling (Rmentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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Regulators of G-protein signalling: multifunctional proteins with impact on signalling in the cardiovascular system

Cited by 120 publications

References 192 publications

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Cellular modelling: experiments and simulation to develop a physiological model of G-protein control of muscarinic K ⁺ channels in mammalian atrial cells

Genetics of arterial hypertension and hypotension

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Regulators of G-protein signalling: multifunctional proteins with impact on signalling in the cardiovascular system

Cited by 120 publications

References 192 publications

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Cellular modelling: experiments and simulation to develop a physiological model of G-protein control of muscarinic K + channels in mammalian atrial cells

Genetics of arterial hypertension and hypotension

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Cellular modelling: experiments and simulation to develop a physiological model of G-protein control of muscarinic K ⁺ channels in mammalian atrial cells