Small Molecule Inhibitors of Regulators of G Protein Signaling (RGS) Proteins

Turner, Emma M.; Blazer, Levi L.; Neubig, Richard R.; Husbands, Stephen M.

doi:10.1021/ml200263y

Cited by 44 publications

(82 citation statements)

References 26 publications

(50 reference statements)

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“…RGS proteins are considered difficult drug targets due to their canonical function of inhibiting signaling through a direct and transient protein-protein interaction with the a subunit of heterotrimeric G proteins (Tesmer et al, 1997). Despite this, significant progress has been made in developing RGS protein inhibitors (Roman et al, 2007;Blazer et al, 2010Blazer et al, , 2011Blazer et al, , 2015Turner et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury

Sjögren

Parra

Atkins

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Regulator of G protein signaling (RGS) proteins have emerged as novel drug targets since their discovery almost two decades ago. RGS2 has received particular interest in cardiovascular research due to its role in regulating G q signaling in the heart and vascular smooth muscle. RGS22/2 mice are hypertensive, prone to heart failure, and display accelerated kidney fibrosis. RGS2 is rapidly degraded through the proteasome, and human mutations leading to accelerated RGS2 protein degradation correlate with hypertension. Hence, stabilizing RGS2 protein expression could be a novel route in treating cardiovascular disease. We previously identified cardiotonic steroids, including digoxin, as selective stabilizers of RGS2 protein in vitro. In the current study we investigated the functional effects of digoxin-mediated RGS2 protein stabilization in vivo. Using freshly isolated myocytes from wild-type and RGS22/2 mice treated with vehicle or low-dose digoxin (2 mg/kg/day for 7 days) we demonstrated that agonist-induced cAMP levels and cardiomyocyte contractility was inhibited by digoxin in wild-type but not in RGS2 2/2 mice. This inhibition was accompanied by an increase in RGS2 protein levels in cardiomyocytes as well as in whole heart tissue. Furthermore, digoxin had protective effects in a model of cardiac injury in wild-type mice and this protection was lost in RGS2 2/2 mice. Digoxin is the oldest known therapy for heart failure; however, beyond its activity at the Na 1 /K 1 -ATPase, the exact mechanism of action is not known. The current study adds a novel mechanism, whereby through stabilizing RGS2 protein levels digoxin could exert its protective effects in the failing heart.

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Section: Introductionmentioning

confidence: 99%

Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury

Sjögren

Parra

Atkins

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Modulation of RGS proteins might alter GPCR signaling in a pathway-and tissue-specific manner (Blazer and Neubig, 2009). Although RGS proteins are considered to be difficult drug targets (Tesmer et al, 1997), we and others have made significant progress in developing RGS protein inhibitors (Roman et al, 2007;Blazer et al, 2010Blazer et al, , 2011Turner et al, 2012). In other cases, however, increasing RGS protein function may be therapeutically beneficial.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, we (Zhong and Neubig, 2001; and others (Doggrell, 2004;Riddle et al, 2005;da Costa Goncalves et al, 2008) suggested that RGS proteins, including RGS2, might represent novel cardiovascular therapeutic targets. Although significant progress has been made in identifying RGS inhibitors (Blazer et al, 2011;Turner et al, 2012), enhancing RGS action is more challenging .…”

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confidence: 99%

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

et al. 2012

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Regulator of G protein signaling 2 (RGS2), a G q -specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(Ϫ/Ϫ) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a ␤-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2-to 3-fold. Na ϩ /K ϩ -ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na ϩ /K ϩ -ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, G qdependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTSinduced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy.

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“…This idea has been bolstered by the intriguing phenotypes observed in mice carrying RGS-insensitive Ga mutants, which showed that blocking RGS actions potentiates neurotransmitter actions and linked behaviors in a targeted fashion (Talbot et al, 2010;Lamberts et al, 2013). While initial efforts focused on the identification and development of peptide inhibitors of RGS proteins as proof of concept (Jin et al, 2004;Wang et al, 2008), more recent work has focused on the development of small molecule inhibitors with the goal of treating multiple diseases, including neurologic disorders (Blazer et al, , 2011Roman and Traynor, 2011;Turner et al, 2012;Storaska et al, 2013). Thus far, RGS4 has been the main focus for the development of small molecule RGS inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

2015

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The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Ga subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre-and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets.

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Small Molecule Inhibitors of Regulators of G Protein Signaling (RGS) Proteins

Cited by 44 publications

References 26 publications

Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury

Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

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