Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior

Gross, Joshua; Kaski, Shane W; Schmidt, Karl T.; Cogan, Elizabeth S.; Boyt, Kristen M.; Wix, Kim; Schroer, Adam B.; McElligott, Zoé A.; Siderovski, David P.; Setola, Vincent

doi:10.1038/s41386-019-0423-7

Cited by 16 publications

(15 citation statements)

References 98 publications

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“…Effects of RU-1205: Initiation of the Intravenous Self-administration Reaction in Mice. analgesic effect without causing dysphoria (Ehrich et al 2015;Gross et al 2019), which either have a multi-targeted effect with the properties of selective kappa agonists and p38 MAPK kinase inhibitors, or are "functionally selective" kappa receptor ligands. The term "functional selectivity" or "biased agonism" describes the ability of a ligand of a G-protein-coupled receptor to selectively activate a subset of signaling cascades in a particular GPCR, as opposed to activating all downstream signaling cascades (eg.…”

Section: Discussionmentioning

confidence: 99%

“…G-proteins, arrestin and/or kinase) (Bruchas et al 2007). It has been suggested that p38 MAPK activation is mediated by β-arrestin-2 signaling, which allows us to consider the therapeutic potential of KOR ligands functionally selective towards G protein and away from β-arrestin2 pathways as analgetics without dysphoric side effects (Gross et al 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Although kappa opioid receptor (KOR) agonists are highly effective analgesics with a low risk of dependence and abuse, the advancement of the kappa opioid ligand class is largely limited to kappa-receptor-specific neuropsychiatric adverse effects, including sedation and dysphoria (Schattauer et al 2017;Gross et al 2019;Margolis and Karkhanis 2019). Currently, there is evidence that kappa agonists that do not activate p38 MAPK kinase (Ehrich et al 2015), the stimulation of which is the cause of kappa-mediated aversive reactions, will not cause dysphoria, sedation and, at the same time, maintain a high enough analgesic efficacy for treating various conditions associated with severe pain (Bruchas et al 2007;White et al 2015;Zan et al 2016;Abraham et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205

Spasov¹,

Zvartau²,

Гречко³

et al. 2020

RRP

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Introduction: The clinical use of kappa-opioid agonists, despite their lack of significant drug potential, is limited by the development of severe sedation, dysphoria, depression, and anhedonia. To this date, there are kappa-opioid receptor agonists lacking these side effects due to the selective activation of intracellular signal transmission pathways without p38-MAPK-kinase activation. Materials and methods: We analyzed assessment of the docking energy of compound RU-1205 to the p38-MAPK active center by the method of similarity to SB203580. The study of possible aversive properties of RU-1205 (0.01–1 mg/kg s.c.) conducted in the tests of the intravenous self-administration and drug differentiation with butorphanol (0.01–0.3 mg/kg). The study of p38 MAPK-inhibitory activity was studied by the ability of RU-1205 to change the aversive properties of U50488 (10 mg/kg i.p.) compared to MAPK-kinase inhibitor SB203580 in the conditioned place avoidance test. Results: The spatial similarity coefficient of the RU-1205 molecule with SB203580 by the molecular conformation method was 1.14 (high similarity), and the docking energy was -8.7 Kcal/mol. RU-1205 did not possess any properties similar to those of butorphanol and did not demonstrate any primary reinforcing aversive properties in the development of intravenous self-administration reaction. Compound RU-1205 did not demonstrate any aversive properties in the conditioned place avoidance test, and reduced the development of aversion caused by U-50488, when they were used together. Discussion: The in silico analysis suggested that, in addition to agonism towards the kappa-opioid receptor, RU-1205 compound exhibits the properties of a p38 MAPK kinase inhibitor, which means it may have a double pharmacological activity. Conclusion: Kappa agonist – compound RU-1205 – is not a trigger of the development of behavioral patterns in animals corresponding to the development of addiction/dysphoria. The mechanism of such an activity may be associated with an inhibitory effect of compound RU-1205 on neuronal p38-MAPK-kinase.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205

Spasov¹,

Zvartau²,

Гречко³

et al. 2020

RRP

View full text Add to dashboard Cite

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“…In PC12 cells stably expressing KOR, agonist application increased RGS4 mRNA expression in a KOR antagonist reversible manner, a process that may contribute to desensitization of KOR agonist responses (Nakagawa et al, 2001). Downstream of KOR, RGS12 attenuates G-protein signaling and promotes β-arrestin (Gross et al, 2019). Since β-arrestin is thought to promote unwanted effects of KOR agonists, including aversion, an inhibitor of RGS12 would be expected to promote G-protein signaling and therefore analgesia without dysphoria, as indicated in Figure 1.…”

Section: The Kappa Opioid Receptormentioning

confidence: 99%

Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management

Senese

Kandasamy

Kochan

et al. 2020

Front. Mol. Neurosci.

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Opioid drugs are the gold standard for the management of pain, but their use is severely limited by dangerous and unpleasant side effects. All clinically available opioid analgesics bind to and activate the mu-opioid receptor (MOR), a heterotrimeric G-protein-coupled receptor, to produce analgesia. The activity of these receptors is modulated by a family of intracellular RGS proteins or regulators of G-protein signaling proteins, characterized by the presence of a conserved RGS Homology (RH) domain. These proteins act as negative regulators of G-protein signaling by serving as GTPase accelerating proteins or GAPS to switch off signaling by both the Gα and βγ subunits of heterotrimeric G-proteins. Consequently, knockdown or knockout of RGS protein activity enhances signaling downstream of MOR. In this review we discuss current knowledge of how this activity, across the different families of RGS proteins, modulates MOR activity, as well as activity of other members of the opioid receptor family, and so pain and analgesia in animal models, with particular emphasis on RGS4 and RGS9 families. We discuss inhibition of RGS proteins with small molecule inhibitors that bind to sensitive cysteine moieties in the RH domain and the potential for targeting this family of intracellular proteins as adjuncts to provide an opioid sparing effect or as standalone analgesics by promoting the activity of endogenous opioid peptides. Overall, we conclude that RGS proteins may be a novel drug target to provide analgesia with reduced opioid-like side effects, but that much basic work is needed to define the roles for specific RGS proteins, particularly in chronic pain, as well as a need to develop newer inhibitors.

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“…RGS12, a member of the RGS protein superfamily (Snow et al, 1997; Snow et al, 1998), is abundantly expressed in the embryonic nervous system (Martin-McCaffrey et al, 2005), and it displays appreciable protein expression within some serotonergic projection regions of the adult mouse brain (e.g. cortex, hippocampus, striatum, midbrain) (Gross et al, 2018; Gross et al, 2019). We have previously shown that stimulation of hyperlocomotion by acute administration of DAT-targeting psychostimulants (AMPH, cocaine) is reduced in RGS12-null mice (Gross et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Genetic deletion ofRgs12in mice affects serotonin transporter expression and functionin vivoandex vivo

et al. 2020

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Background: Regulator of G protein Signaling (RGS) proteins inhibit G protein-coupled receptor (GPCR) signaling, including the signals that arise from neurotransmitter release. We have shown that RGS12 loss diminishes locomotor responses of C57BL/6J mice to dopamine transporter (DAT)-targeting psychostimulants. This diminution resulted from a brain region-specific upregulation of DAT expression and function in RGS12-null mice. This effect on DAT prompted us to investigate whether the serotonin transporter (SERT) exhibits similar alterations upon RGS12 loss in C57BL/6J mice. Aims: Does RGS12 loss affect (a) hyperlocomotion to the preferentially SERT-targeting psychostimulant 3,4-methylenedioxymethamphetamine (MDMA), (b) SERT expression and function in relevant brain regions, and/or (c) serotonergically modulated behaviors? Methods: Open-field and spontaneous home-cage locomotor activities were quantified. 5-HT, 5-HIAA, and SERT levels in brain-region homogenates, as well as SERT expression and function in brain-region tissue preparations, were measured using appropriate biochemical assays. Serotonergically modulated behaviors were assessed using forced swim and tail suspension paradigms, elevated plus and elevated zero maze tests, and social interaction assays. Results: RGS12-null mice displayed no hyperlocomotion to 10 mg/kg MDMA. There were brain region-specific alterations in SERT expression and function associated with RGS12 loss. Drug-naïve RGS12-null mice displayed increases in both anxiety-like and anti-depressive-like behaviors. Conclusion: RGS12 is a critical modulator of serotonergic neurotransmission and serotonergically modulated behavior in mice; lack of hyperlocomotion to low dose MDMA in RGS12-null mice is related to an alteration of steady-state SERT expression and 5-HT uptake.

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Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior

Cited by 16 publications

References 98 publications

Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205

Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205

Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management

Genetic deletion ofRgs12in mice affects serotonin transporter expression and functionin vivoandex vivo

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