The Gβ<sub>5</sub>−RGS7 Complex Selectively Inhibits Muscarinic M3 Receptor Signaling via the Interaction between the Third Intracellular Loop of the Receptor and the DEP Domain of RGS7

Sandiford, Simone L.; Slepak, Vladlen Z.

doi:10.1021/bi801989c

Cited by 41 publications

(76 citation statements)

References 58 publications

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“…First, our results showed a direct interaction between G␤5 and ␤-arrestin2 in a GST pulldown assay (data not shown). As reported previously (33,38), G␤5 interacted with the DEP domain and this interaction was ␤-arrestin2 dependent (Fig. 7D).…”

Section: Rgs9supporting

confidence: 87%

“…As shown in In accordance with these results, the crystal structure of the G␤5-RGS9 complex shows that the DEP domain is positioned at a location remote from the plasma membrane where GPCR and RGS9-2 form a complex (8). Similar findings on the functional role of the DEP domain were reported for inhibition of the endocytosis of the opioid receptor by RGS9-2 (34) and inhibition of the signaling of the M3 muscarinic receptor by RGS7 (38), a member of the R7 family of RGS proteins to which RGS9-2 belongs. As in these studies, the DEP domain, rather than the catalytic activity of GTPase activation through the RGS domain, seems to determine the inhibitory effect of RGS9-2 on the signaling of D 3 R. Intermediate components could be involved in the inhibitory effect of RGS9-2 on the signaling of D 3 R. Results in Fig.…”

Section: Rgs9supporting

confidence: 85%

“…A key question remaining is what controls the conversion from the inactive to the active conformation? Although previous studies have suggested that the interaction between the intracellular receptor regions of the M3 muscarinic receptor and the DEP domain of RGS7 contribute to the conversion between the open and closed states (38,39), it is still not clear whether there is a common intermediate cellular component that connects the DEP domain and the receptor regions.…”

mentioning

confidence: 97%

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β-Arrestin2 Plays Permissive Roles in the Inhibitory Activities of RGS9-2 on G Protein-Coupled Receptors by Maintaining RGS9-2 in the Open Conformation

Zheng

Cheong

Min

et al. 2011

Molecular and Cellular Biology

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Together with G protein-coupled receptor (GPCR) kinases (GRKs) and ␤-arrestins, RGS proteins are the major family of molecules that control the signaling of GPCRs. The expression pattern of one of these RGS family members, RGS9-2, coincides with that of the dopamine D 3 receptor (D 3 R) in the brain, and in vivo studies have shown that RGS9-2 regulates the signaling of D2-like receptors. In this study, ␤-arrestin2 was found to be required for scaffolding of the intricate interactions among the dishevelled-EGL10-pleckstrin (DEP) domain of RGS9-2, G␤5, R7-binding protein (R7BP), and D 3 R. The DEP domain of RGS9-2, under the permission of ␤-arrestin2, inhibited the signaling of D 3 R in collaboration with G␤5. ␤-Arrestin2 competed with R7BP and G␤5 so that RGS9-2 is placed in the cytosolic region in an open conformation which is able to inhibit the signaling of GPCRs. The affinity of the receptor protein for ␤-arrestin2 was a critical factor that determined the selectivity of RGS9-2 for the receptor it regulates. These results show that ␤-arrestins function not only as mediators of receptor-G protein uncoupling and initiators of receptor endocytosis but also as scaffolding proteins that control and coordinate the inhibitory effects of RGS proteins on the signaling of certain GPCRs.The regulation of G protein-coupled receptors (GPCRs) involves various cellular events in different time frames, and the detailed regulatory mechanism can be unique for each receptor type and the signal it mediates. Much of our knowledge concerning the molecular basis of homologous desensitization of GPCRs is derived from studies of the ␤ 2 -adrenergic receptor (␤ 2 AR), in which GPCR kinases (GRKs) and ␤-arrestins play central roles. According to this working model, GRK-mediated receptor phosphorylation, followed by the association of ␤-arrestin, causes uncoupling of the GPCR from the G protein (16,18,30). However, the detailed molecular mechanism of this uncoupling of receptors from the G protein is unclear, aside from the simple idea that ␤-arrestins could physically interfere with the interaction between the receptor and G protein.Upon agonist binding, GPCRs stimulate the conversion of the inactive heterotrimeric GTP-binding protein GDP-G␣␤␥ to GTP-G␣ and G␤␥. The duration of the active state of the G protein, GTP-G␣, is regulated by two different cellular components, the weak GTPase activity of G␣ itself and the catalytic activity of GTPase-activating proteins (GAPs). Regulators of G protein signaling (RGS) act as GAPs for the heterotrimeric G protein ␣ subunit (49). More than 30 RGS proteins have been discovered over the last decade, and they are divided into 8 subfamilies (11,26,52).Among these RGS proteins, RGS2, RGS4, and RGS9-2 are known to be mutually related to the dopaminergic nervous system. It is known that the expression of the genes for RGS2 and RGS4 changes in response to dopaminergic stimulation (43, 44); however, the roles of RGS2 and RGS4 in the signaling and intracellular trafficking of D 2 R and D 3 R have not been...

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Section: Rgs9supporting

confidence: 87%

Section: Rgs9supporting

confidence: 85%

mentioning

confidence: 97%

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β-Arrestin2 Plays Permissive Roles in the Inhibitory Activities of RGS9-2 on G Protein-Coupled Receptors by Maintaining RGS9-2 in the Open Conformation

Zheng

Cheong

Min

et al. 2011

Molecular and Cellular Biology

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“…However, it is becoming increasingly appreciated that, in vivo, RGS proteins function in a tight association with other components of the GPCR signaling cascades and exist in larger macromolecular complexes (29). For example, both RGS7 and RGS9 form complexes with a range of partners that include G␤5; the membrane anchors R7BP and R9AP (30); and the GPCRs mGlur6 (31), D2R (13,32), MOR (33)(34)(35), m3 muscarinic (36), and GPR158/179 (37). Nevertheless, how these interactions shape RGS action in cells is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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

Xie

Martemyanov

2013

Journal of Biological Chemistry

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Background: RGS7 and RGS9-2 regulate G protein signaling in the striatum, but the selectivity of their action is largely unknown. Results: RGS protein complexes show distinct patterns of receptor and G protein selectivity. Conclusion: Macromolecular composition dictates receptor and G protein selectivity of the RGS7 and RGS9-2 protein complexes.Significance: These data demonstrate novel mechanisms contributing to the regulation of striatal G protein signaling.

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“…Gβ 5 interaction with the GGL domain of R7 protein regulates protein stability and is described below. Additional interactions between the DEP domain and intracellular regions of GPCRs have also been demonstrated (Sandiford and Slepak, 2009) providing additional mechanisms whereby this family of RGS proteins can regulate GPCR signalling in a non-canonical manner.…”

Section: Additional Domains and Non-canonical Functions Of Rgs Proteinsmentioning

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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The Gβ₅−RGS7 Complex Selectively Inhibits Muscarinic M3 Receptor Signaling via the Interaction between the Third Intracellular Loop of the Receptor and the DEP Domain of RGS7

Cited by 41 publications

References 58 publications

β-Arrestin2 Plays Permissive Roles in the Inhibitory Activities of RGS9-2 on G Protein-Coupled Receptors by Maintaining RGS9-2 in the Open Conformation

β-Arrestin2 Plays Permissive Roles in the Inhibitory Activities of RGS9-2 on G Protein-Coupled Receptors by Maintaining RGS9-2 in the Open Conformation

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

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

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The Gβ5−RGS7 Complex Selectively Inhibits Muscarinic M3 Receptor Signaling via the Interaction between the Third Intracellular Loop of the Receptor and the DEP Domain of RGS7

Cited by 41 publications

References 58 publications

β-Arrestin2 Plays Permissive Roles in the Inhibitory Activities of RGS9-2 on G Protein-Coupled Receptors by Maintaining RGS9-2 in the Open Conformation

β-Arrestin2 Plays Permissive Roles in the Inhibitory Activities of RGS9-2 on G Protein-Coupled Receptors by Maintaining RGS9-2 in the Open Conformation

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

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

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The Gβ₅−RGS7 Complex Selectively Inhibits Muscarinic M3 Receptor Signaling via the Interaction between the Third Intracellular Loop of the Receptor and the DEP Domain of RGS7