RGS9–2 Negatively Modulates l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease

Gold, Stephen J.; Hoang, C.; Potts, Bryan W.; Porras, Grégory; Pioli, Elsa Y.; Kim, Ki Woo; Nadjar, Agnès; Qin, Chuan; LaHoste, Gerald J.; Li, Qin; Bioulac, Bernard; Waugh, Jeff L.; Gurevich, Eugenia V.; Neve, Rachael L.; Bézard, Erwan

doi:10.1523/jneurosci.4223-07.2007

Cited by 115 publications

(108 citation statements)

References 56 publications

(85 reference statements)

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“…Recent evidence from genetic mouse models suggests that R7BP has a key role in regulation of GPCR responses in the basal ganglia, via interactions with RGS9-2 and RGS7. RGS9-2 is expressed in very high amounts in the striatum, where it has been shown to modulate responsiveness of m-opioid and D2 dopamine GPCRs Zachariou et al, 2003;CabreraVera et al, 2004;Kovoor et al, 2005;Gold et al, 2007;Traynor et al, 2009). Specifically, our earlier work revealed a potent role of RGS9-2 in opiate actions Psifogeorgou et al, 2007;Psifogeorgou et al, 2011).…”

Section: Introductionmentioning

confidence: 72%

R7BP Modulates Opiate Analgesia and Tolerance but not Withdrawal

Terzi

Cao

Agrimaki

et al. 2011

Neuropsychopharmacol

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The adaptor protein R7 family binding protein (R7BP) modulates G protein coupled receptor (GPCR) signaling and desensitization by controlling the function of regulator of G protein signaling (RGS) proteins. R7BP is expressed throughout the brain and appears to modulate the membrane localization and stability of three proteins that belong to R7 RGS family: RGS6, RGS7, and RGS9-2. RGS9-2 is a potent negative modulator of opiate and psychostimulant addiction and promotes the development of analgesic tolerance to morphine, whereas the role of RGS6 and RGS7 in addiction remains unknown. Recent studies revealed that functional deletion of R7BP reduces R7 protein activity by preventing their anchoring to the cell membrane and enhances GPCR responsiveness in the basal ganglia. Here, we take advantage of R7BP knockout mice in order to examine the way interventions in R7 proteins function throughout the brain affect opiate actions. Our results suggest that R7BP is a negative modulator of the analgesic and locomotor activating actions of morphine. We also report that R7BP contributes to the development of morphine tolerance. Finally, our data suggest that although prevention of R7BP actions enhances the analgesic responses to morphine, it does not affect the severity of somatic withdrawal signs. Our data suggest that interventions in R7BP actions enhance the analgesic effect of morphine and prevent tolerance, without affecting withdrawal, pointing to R7BP complexes as potential new targets for analgesic drugs.

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Section: Introductionmentioning

confidence: 72%

R7BP Modulates Opiate Analgesia and Tolerance but not Withdrawal

Terzi

Cao

Agrimaki

et al. 2011

Neuropsychopharmacol

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“…One example is RGS9-2, which is specifically enriched in striatum (Mancuso et al, 2009) [an alternative isoform, RGS9-1, is exclusively expressed in photoreceptor cells in the retina (He et al, 1998)]. This selective distribution matches the critical site of L-DOPA-induced dyskinesia, and the Gα i/o -protein selectivity of RGS9 GAP activity corresponds to the Gα i/o coupling of the dopamine D 2 receptor, which is critical in mediating L-DOPA effects in the striatum (Gold et al, 2007;Blundell et al, 2008). The broad distribution of D 2 receptor expression limits the use of D 2 receptor targeted approaches to regulate striatal signalling pathways.…”

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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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“…Despite these drawbacks, L-DOPA is still the mainstay of PD treatment for its unsurpassed antiparkinsonian efficacy. Studies in animal models of PD suggest that dyskinesias are associated with enhanced G protein-mediated signaling at dopamine receptors (17)(18)(19)(20)(21)(22)(23) potentially leading to changes in gene expression and uncontrolled neuronal excitability (21,(24)(25)(26)(27)(28). Therefore, PD therapy strategies that moderate G protein signaling and neuronal excitability while maintaining normal movement may be an ideal way to eliminate DA receptor-associated dyskinesias.…”

mentioning

confidence: 99%

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Urs¹,

Bido

Peterson³

et al. 2015

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

105

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Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G proteinmediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.is a major catecholamine neurotransmitter that is released by midbrain DA neurons. DA activates G protein-coupled receptors (GPCRs), which belong to the dopamine D1 (D1R and D5R) or D2 (D2R, D3R, and D4R) class of DA receptors that are known to signal via G protein-dependent mechanisms (1, 2). However, recent studies have shown that in addition to G protein-mediated signaling, many GPCRs, including DA receptors, signal through beta-arrestin 1 and 2 (βarr1 and βarr2)-dependent mechanisms (3, 4). The two isoforms of β-arrestin, β-arrestin1 (βarr1) and β-arrestin2 (βarr2) are widely coexpressed in the brain (5, 6). β-Arrestins were originally appreciated for their ability to desensitize (i.e., turn off) GPCR signaling in a GPCR kinase (GRK)-dependent manner (7,8). Binding of β-arrestin to the GPCR sterically hinders G protein binding and in most instances initiates receptor endocytosis via interactions with adaptor protein complex-2 (AP-2) and clathrin (9-11). It is now appreciated that β-arrestins regulate physiology and behaviors independently of G protein signaling through their ability to scaffold multiple intracellular signaling molecules such as kinases and phosphatases (3,4,12,13). Studies from our laboratory have shown that through ...

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RGS9–2 Negatively Modulates l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease

Cited by 115 publications

References 56 publications

R7BP Modulates Opiate Analgesia and Tolerance but not Withdrawal

R7BP Modulates Opiate Analgesia and Tolerance but not Withdrawal

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

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

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