RGS4 Inhibits Signaling by Group I Metabotropic Glutamate Receptors

Saugstad, Julie A.; Marino, Michael J.; Folk, Julie A.; Hepler, John R.; Conn, P. Jeffrey

doi:10.1523/jneurosci.18-03-00905.1998

Cited by 130 publications

(97 citation statements)

References 62 publications

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“…Thus, Rgs4 shows complex brain region-, context-, and treatment-specific regulation, consistent with its modulation of numerous GPCRs, including several adrenergic, dopaminergic, serotonergic, opiate, muscarinic, and metabotropic glutamate receptors (mGluRs), which are either Gαi or Gαq coupled (2-9, 31, 32). Further work is needed to understand the complex interactions between Rgs4 and several other signaling proteins that control receptor function (2,8,9,18,30,31) and how these mechanisms influence therapeutic-like responses to monoamine-based antidepressant medications.…”

Section: Twice a Day) (A) Dmi Reduces The Latency To Eat Food From Tmentioning

confidence: 99%

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

Stratinaki

Varidaki

Mitsi

et al. 2013

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

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Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4 , including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.

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Section: Twice a Day) (A) Dmi Reduces The Latency To Eat Food From Tmentioning

confidence: 99%

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

Stratinaki

Varidaki

Mitsi

et al. 2013

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

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“…His 10 RGS2 was expressed in BL21/DE3 and purified as described (20) yielding Ͼ90% purity. His 6 RGS4box (aa 58 -177) was expressed in JM109 and purified under denaturing conditions as described by Popov et al (21).…”

Section: Materials-guanosinementioning

confidence: 99%

A Spatial Focusing Model for G Protein Signals

Zhong¹,

Wade²,

Woolf³

et al. 2003

Journal of Biological Chemistry

116

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Regulators of G protein signaling (RGS) are GTPaseaccelerating proteins (GAPs), which can inhibit heterotrimeric G protein pathways. In this study, we provide experimental and theoretical evidence that high concentrations of receptors (as at a synapse) can lead to saturation of GDP-GTP exchange making GTP hydrolysis rate-limiting. This results in local depletion of inactive heterotrimeric G-GDP, which is reversed by RGS GAP activity. Thus, RGS enhances receptor-mediated G protein activation even as it deactivates the G protein. A critical question in cellular signaling is what determines the specificity of signal transduction processes. There is much recent evidence for the formation of complexes maintained by protein scaffolds to control signaling specificity. This contrasts with a classical model in the G protein signaling field, the collision-coupling model (1), which relies entirely on the structure of receptor-G protein and G protein-effector contact sites to determine signaling specificity. The collision coupling model also suggests that there would be significant spread of G protein signals in a cell upon receptor activation, since all components are freely diffusable. There have been numerous studies indicating that such free transfer of information over long distances may not occur for G i or G q mediated signals (2, 3). Thus, similar to the localized signaling by postsynaptic ionotropic receptors via protein complex assembly (4), mechanisms to limit the "spread" of G protein signaling appear necessary.G protein-coupled receptors (GPCR) 1 activate cellular signals by inducing nucleotide exchange on the G protein ␣ subunit, while inactivation occurs upon GTP hydrolysis by the intrinsic G␣ GTPase (5). Regulator of G protein signaling (RGS) proteins are a recently discovered family of proteins which act as GTPase-activating proteins (GAPs) for G␣ subunits (6 -9). The GAP activity of RGS proteins generally reduces steady state levels of GTP-bound G␣ subunits and inhibits the activity of G proteins (6, 10). However, some studies of receptor-stimulated signaling show that RGS proteins can speed the kinetics of responses without compromising steady state signaling strength (11-13). The mechanism and significance of this paradoxical result is not understood.The maintained signaling in the face of RGS-enhanced GTPase activity suggests that the RGS proteins somehow increase the efficiency of G protein activation. One possible mechanism for this could be "physical scaffolding" in which the RGS protein binds to both receptor and G protein and stabilizes a complex between them. This could involve the diverse aminoand carboxyl-terminal domains of the RGS proteins such as GGL, DEP, DH/PH, and PDZ domains (6,10,14,15). Indeed, RGS12 does bind to the carboxyl terminus of the IL8 receptor through a PDZ domain (16). Alternatively, Ross and co-workers (17) have suggested that the GAP activity of phospholipase C-␤1, which is both a G q GAP and its effector, serves to enhance muscarinic receptor-G q coupling (6,17). In that ...

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“…2ϩ Signaling by RGS4 in Permeable CellsPrevious studies showed that RGS4 added to isolated membranes (28,29) or overexpressed in cell lines (24 -27) inhibited G q -dependent PLC␤ activation. Fig.…”

Section: Inhibition Of Camentioning

confidence: 99%

“…RGS4 inhibited G q -dependent PLC␤ activation in Xenopus oocytes and transfected COS and HEK293 cells (24 -27). Furthermore, addition of recombinant RGS4 protein to NG-108 cell membranes inhibited G q -dependent PLC␤ activity (28,29). RGS2 was reported as a specific GAP for G␣ q in an in vitro assay (30), although it inhibited G i -dependent signaling when expressed in transfected cells (31).…”

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RGS Proteins Determine Signaling Specificity of Gq-coupled Receptors

Xu¹,

Zeng²,

Попов³

et al. 1999

Journal of Biological Chemistry

247

167

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Regulators of G protein signaling (RGS) proteins accelerate GTP hydrolysis by G␣ subunits, thereby attenuating signaling. RGS4 is a GTPase-activating protein for G i and G q class ␣ subunits. In the present study, we used knockouts of G q class genes in mice to evaluate the potency and selectivity of RGS4 in modulating Ca 2؉ signaling transduced by different G q -coupled receptors. RGS4 inhibited phospholipase C activity and Ca 2؉ signaling in a receptor-selective manner in both permeabilized cells and cells dialyzed with RGS4 through a patch pipette. Receptor-dependent inhibition of Ca 2؉ signaling by RGS4 was observed in acini prepared from the rat and mouse pancreas. The response of mouse pancreatic acini to carbachol was about 4-and 33-fold more sensitive to RGS4 than that of bombesin and cholecystokinin (CCK), respectively. RGS1 and RGS16 were also potent inhibitors of G q -dependent Ca 2؉ signaling and acted in a receptor-selective manner. RGS1 showed approximately 1000-fold higher potency in inhibiting carbachol than CCK-dependent signaling. RGS16 was as effective as RGS1 in inhibiting carbachol-dependent signaling but only partially inhibited the response to CCK. By contrast, RGS2 inhibited the response to carbachol and CCK with equal potency. The same pattern of receptorselective inhibition by RGS4 was observed in acinar cells from wild type and several single and double G q class knockout mice. Thus, these receptors appear to couple G q class ␣ subunit isotypes equally. Difference in receptor selectivity of RGS proteins action indicates that regulatory specificity is conferred by interaction of RGS proteins with receptor complexes.

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RGS4 Inhibits Signaling by Group I Metabotropic Glutamate Receptors

Cited by 130 publications

References 62 publications

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

A Spatial Focusing Model for G Protein Signals

RGS Proteins Determine Signaling Specificity of Gq-coupled Receptors

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