Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure

Mittmann, Clemens; Chung, Chin Hee; Höppner, Grit; Michalek, Christina; Nose, Monika; Schüler, Christian; Schuh, Antje; Eschenhagen, Thomas; Weil, Joachim; Pieske, Burkert; Hirt, Stephan; Wieland, Thomas

doi:10.1016/s0008-6363(02)00459-5

Cited by 101 publications

(83 citation statements)

References 39 publications

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“…In the past two decades, RGS proteins have received increasing interest as potential drug targets in numerous therapeutic areas, including cardiovascular disease, multiple CNS disorders and several types of cancer (Mittmann et al, 2002;Riddle et al, 2005;Hurst and Hooks, 2009;Sjögren et al, 2010). While GPCR signalling has been a major focus in drug development, traditional GPCR agonists and antagonists are often associated with side effects due to widespread expression of many receptors and lack of receptor selectivity of drugs.…”

Section: Why Target Rgs Proteins In Drug Discovery?mentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

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Section: Why Target Rgs Proteins In Drug Discovery?mentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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“…RGS2-RGS5 are thought to be important in the heart (5,6), although their precise roles remain unclear. Human heart failure is associated with increased RGS4 expression, whereas expression of RGS2 is unchanged (7). Forced overexpression of RGS4 blunts G q -stimulated cardiac hypertrophy in rat neonatal cardiac myocytes (8) and intact hearts (9) and suppresses cardiac hypertrophy of transgenic mice lacking guanylate cyclase-A (natriuretic peptide-stimulated cyclase; ref.…”

Section: Introductionmentioning

confidence: 99%

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

Takimoto¹,

Koitabashi²,

Hsu³

et al. 2009

J. Clin. Invest.

139

174

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The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. G q protein-coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial G q signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by G q activation, induced a normal cardiac response, while Rgs2 deletion in G αq -overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing G q -stimulated vascular contraction. In normal mice, but not Rgs2 -/-mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting G q -coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2 -/-myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors.

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“…Previous studies demonstrated a complete lack of correlation between RGS4 messenger RNA and protein levels in metastatic breast cancer cells due to its rapid proteasomal degradation (10). Although it has been reported that RGS4 facilitates breast cancer invasiveness and growth both in vitro and in vivo, its function on the cell cycle has not been explored thus far (8). In the present study, breast cancer cell lines were transfected with a recombinant cDNA plasmid containing the open reading frame of RGS4.…”

Section: Discussionmentioning

confidence: 89%

“…Proteins of the RGS family modulate GPCR-mediated signals in cells (5). Among the >20 RGS proteins known to date, RGS4, a GAP for heterotrimeric Gq and Gi (7), is associated with regulation of the hypertrophic response in the failing human myocardium (8,9) and with the regulation of migration and invasion in breast cancer (10). RGS4 has an N-terminal Cys residue that is targeted for ubiquitin-dependent degradation by arginylation through the Arg/N-end rule pathway of protein degradation (11,12).…”

Section: Introductionmentioning

confidence: 99%

Growth inhibition of human breast carcinoma cells by overexpression of regulator of G-protein signaling 4

2017

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Abstract. Breast cancer remains the second largest cause of mortality in women with cancer and does not respond well to conventional therapies. Regulator of G-protein signaling 4 (RGS4) is a GTPase-activating protein of the heterotrimeric Gq and Gi proteins. Altered levels of RGS4 are reportedly linked with several human diseases, including cancer. The present study investigated whether overexpression of RGS4 inhibited the growth of human breast cancer cells. Protein expression was investigated by western blot analysis. Cell viability and apoptosis were analyzed by MTT assay and flow cytometric analysis, respectively. Cell cycle analysis was performed using propidium iodide staining in order to examine the anti-proliferative function of increased RGS4 levels. Next, changes in the expression levels of G 2 /M cell cycle-related proteins were examined. Overexpression of RGS4 led to the upregulation of phosphorylayed (p)-Ser 216 cell division cycle (Cdc)25C and p-Tyr 15 Cdc2. Importantly, MG132-induced proteasome blockade prevented degradation of RGS4. Suppression of proliferation was associated with G 2 /M-phase cell cycle arrest. Furthermore, enhanced endogenous RGS4 protein levels significantly inhibited breast cancer cell growth, which was reversed by a pharmacological inhibitor of RGS4. Taken together, these results suggest that overexpression of RGS4 in human breast cancer cells by molecular means may offer a potential therapeutic approach.

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Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure

Abstract: The upregulation of RGS4 in failing human myocardium diminishes Gq/11-mediated signalling and can be involved in the desensitization of Gq/11-mediated positive inotropic effects.

Cited by 101 publications

References 39 publications

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

Growth inhibition of human breast carcinoma cells by overexpression of regulator of G-protein signaling 4

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