Macromolecular Composition Dictates Receptor and G Protein Selectivity of Regulator of G Protein Signaling (RGS) 7 and 9-2 Protein Complexes in Living Cells

Masuho, Ikuo; Xie, Keqiang; Martemyanov, Kirill A.

doi:10.1074/jbc.m113.462283

Cited by 49 publications

(63 citation statements)

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“…Although most RGS proteins can act on almost all of the Gα subunits in the Gαi/o and Gq family, different RGS proteins have their own selectivity for Gα subunits. For example, RGS9 proteins show a bias toward Gαo over Gαi in the presence of the binding partner Gβ5 whereas RGS7 proteins only regulate Gαo signaling as determined by kinetics of GTP hydrolysis in HEK293 cells [25]. Neither RGS9 nor RGS7 proteins exhibit selectivity for Gq in this heterologous expression system.…”

Section: Rgs Proteins: Function and Brain Expressionmentioning

confidence: 99%

Dysregulation of RGS Proteins by Psychostimulants

2014

J Addict & Prev

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Regulator of G protein signaling (RGS) proteins are a class of proteins that negatively modulate GPCR-mediated G protein signaling. The distribution of subtypes of RGS proteins is brain region specific. Several subtypes of RGS proteins are present in the mesolimbic dopaminergic pathway and are subjected to modulation by psychostimulants. Acute or chronic exposure to psychostimulants induces changes in mRNA levels of RGS in a subtype-, brain region-, and time-dependent manner. The dynamic changes in the abundance of RGS proteins by psychostimulant treatment may be associated with dopamine receptor sensitization or desensitization, a potential mechanism underlying drug sensitization or tolerance. Small molecule RGS inhibitors are useful tools for studying in vivo function of RGS proteins and are potential therapeutics for the treatment of psychostimulant addiction.

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Section: Rgs Proteins: Function and Brain Expressionmentioning

confidence: 99%

Dysregulation of RGS Proteins by Psychostimulants

2014

J Addict & Prev

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“…Cells were transfected at ϳ80% confluence in 35-mm plates using Lipofectamine PLUS (2.5 l) and LTX (4 l) reagents for Bioluminescence Resonance Energy Transfer assay as previously described with modification (34). MOR, G␣oA, Venus155-239-G␤1, Venus1-155-G␥2, masGRK3ct-Nluc, and SNAP f -KRas constructs were transfected at a 1:2:1:1:1:1 ratio.…”

Section: Methodsmentioning

confidence: 99%

“…In this assay (34,38), NG108 -15 cells are transfected with -opioid receptor (MOR) together with G␣o, a preferred substrate of RGS7 and RGS9 -2, and reporter constructs G␤␥-Venus, and GRK3ct-Nluc ( Fig. 2A).…”

Section: Real-time Reversible System For Rapid Membrane Recruitment Amentioning

confidence: 99%

“…The RGS7/G␤5 and RGS9 -2/G␤5 complexes can be effectively recruited to the plasma membrane via interaction with their substrate, activated G␣o (33) or membrane anchors R7BP (20,24) and GPR158 (27). In the case of R7BP, this membrane recruitment has been reported to result in augmentation of RGS9 -2 and RGS7 GAP activity toward its substrates G␣i and G␣o, accelerating termination of the G protein driven responses (21,34). The mechanism behind this stimulatory effect is unclear.…”

mentioning

confidence: 99%

“…The mechanism behind this stimulatory effect is unclear. On the one hand, membrane recruitment of RGS proteins may facilitate G protein deactivation by increasing the proximity to of RGS proteins to their membrane-bound substrate G␣-GTP (21,27,34). On the other hand, R7BP has been also proposed to act as an allosteric modulator of RGS proteins (35,36).…”

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Association with the Plasma Membrane Is Sufficient for Potentiating Catalytic Activity of Regulators of G Protein Signaling (RGS) Proteins of the R7 Subfamily

Muntean

Martemyanov

2016

Journal of Biological Chemistry

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Regulators of G protein Signaling (RGS) promote deactivation of heterotrimeric G proteins thus controlling the magnitude and kinetics of responses mediated by G protein-coupled receptors (GPCR).In the nervous system, RGS7 and RGS9 -2 play essential role in vision, reward processing, and movement control. Both RGS7 and RGS9 -2 belong to the R7 subfamily of RGS proteins that form macromolecular complexes with R7-binding protein (R7BP). R7BP targets RGS proteins to the plasma membrane and augments their GTPase-accelerating protein (GAP) activity, ultimately accelerating deactivation of G protein signaling. However, it remains unclear if R7BP serves exclusively as a membrane anchoring subunit or further modulates RGS proteins to increase their GAP activity. To directly answer this question, we utilized a rapidly reversible chemically induced protein dimerization system that enabled us to control RGS localization independent from R7BP in living cells. To monitor kinetics of G␣ deactivation, we coupled this strategy with measuring changes in the GAP activity by bioluminescence resonance energy transfer-based assay in a cellular system containing -opioid receptor. This approach was used to correlate changes in RGS localization and activity in the presence or absence of R7BP. Strikingly, we observed that RGS activity is augmented by membrane recruitment, in an orientation independent manner with no additional contributions provided by R7BP. These findings argue that the association of R7 RGS proteins with the membrane environment provides a major direct contribution to modulation of their GAP activity.In the nervous system, signaling through transmembrane G protein-coupled receptors (GPCRs) 2 plays a crucial role in a number of fundamental processes including differentiation, neurotransmission, and synaptic plasticity (1). Upon binding to an extracellular ligand, GPCRs undergo a conformational change that leads to activation of intracellular heterotrimeric G␣␤␥ proteins. This process involves dissociation of G proteins into G␣GTP and G␤␥ subunits freeing them for the interaction with downstream effectors (2). The magnitude of the response depends on the amount of time G proteins spend in their activated state. Therefore, timely deactivation of G proteins is crucial for determining the overall extent of signaling.Deactivation of G proteins is controlled by Regulators of G protein signaling (RGS) proteins which act as GTPase-activating proteins (GAPs) accelerating the rate of GTP hydrolysis on the G␣ subunit thereby promoting return of G protein to its inactive G␣␤␥ heterotrimeric state. It is currently well accepted that the RGS-catalyzed G protein deactivation is essential for determining timing, extent and sensitivity of G protein signaling in a number of GPCR pathways (3, 4). Among more than 30 known RGS proteins in mammalian genomes, critical roles for the signaling in the nervous system has been attributed to the R7 family that includes RGS6, RGS7, RGS9, and RGS11. Two members of the R7 family in particular, RGS7 an...

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G alpha o

Iguchi¹,

Kasahara²

2016

Encyclopedia of Signaling Molecules

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Macromolecular Composition Dictates Receptor and G Protein Selectivity of Regulator of G Protein Signaling (RGS) 7 and 9-2 Protein Complexes in Living Cells

Cited by 49 publications

References 41 publications

Dysregulation of RGS Proteins by Psychostimulants

Dysregulation of RGS Proteins by Psychostimulants

Association with the Plasma Membrane Is Sufficient for Potentiating Catalytic Activity of Regulators of G Protein Signaling (RGS) Proteins of the R7 Subfamily

G alpha o

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