Integration of G Protein α (Gα) Signaling by the Regulator of G Protein Signaling 14 (RGS14)

Brown, Nicole; Goswami, Devrishi; Branch, Mary Rose; Ramineni, Suneela; Ortlund, Eric A.; Griffin, Patrick R.; Hepler, John R.

doi:10.1074/jbc.m114.634329

Cited by 31 publications

(94 citation statements)

References 53 publications

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“…Recent evidence suggests that the RGS domain of RGS14 maintains GAP activity when its GPR motif is bound to inactive Ga i subunits at the plasma membrane (Brown et al, 2015). This supports a model (Brown et al, 2015) in which cytosolic RGS14 could be recruited initially to the postsynaptic density through its RGS domain following GPCR and Ga i activation, where its GPR motif captures the resulting inactive Ga i -GDP (Fig. 1C).…”

Section: Rgs14supporting

confidence: 65%

“…1C). In this way, the newly formed RGS14:Ga i complex is properly placed to GAP other nearby Ga i/o -GTP enabling those resulting Ga i -GDP to recruit and cluster additional RGS14:Ga i complexes to form a signaling node at or near the plasma membrane and possibly the postsynaptic density (Brown et al, 2015). In this speculative scenario, RGS14 would be well positioned to intercept local signals necessary for the induction of LTP, such as H-Ras activation of ERK and/or calcium-activated calmodulin activation of CaMKII.…”

Section: Rgs14mentioning

confidence: 99%

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Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

2015

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The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Ga subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre-and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets.

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Section: Rgs14supporting

confidence: 65%

Section: Rgs14mentioning

confidence: 99%

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

2015

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“…RGS12 and RGS14 are two of the largest classical RGS proteins with additional domains apart from the RGS and GoLoco domains. Notably, the Ras binding domain(s) present in these proteins has been demonstrated to integrate GPCR and Ras/MAPK signalling pathways (Shu et al, 2010;Zhao et al, 2013;Brown et al, 2015). Furthermore, through an additional domain, the phosphotyrosine binding (PTB) domain, RGS12 can interact with, and modulate the activity of, N-type calcium channels in a phosphorylation-dependent manner (Schiff et al, 2000).…”

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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“…Importantly, the combination of HDX-MS information with high-resolution structural approaches will allow for a much more detailed view of the structural and dynamic determinants of how these systems are regulated. Recent years have seen a number of extremely complicated lipid signalling systems, including a variety of integral membrane protein complexes, probed by HDX-MS, including many important studies defining the regulation of GPCRs [18,[88][89][90]. This is highlighted by studies on the mechanism of nt release of G proteins downstream of GPCRs [90], as well as the mechanism of GPCR down-regulation by β-arrestin recruitment [18].…”

Section: Studying Membrane Proteins By Hdx-msmentioning

confidence: 98%

Probing the dynamic regulation of peripheral membrane proteins using hydrogen deuterium exchange–MS (HDX–MS)

Vadas

Burke

2015

Biochemical Society Transactions

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Many cellular signalling events are controlled by the selective recruitment of protein complexes to membranes. Determining the molecular basis for how lipid signalling complexes are recruited, assembled and regulated on specific membrane compartments has remained challenging due to the difficulty of working in conditions mimicking native biological membrane environments. Enzyme recruitment to membranes is controlled by a variety of regulatory mechanisms, including binding to specific lipid species, protein-protein interactions, membrane curvature, as well as post-translational modifications. A powerful tool to study the regulation of membrane signalling enzymes and complexes is hydrogen deuterium exchange-MS (HDX-MS), a technique that allows for the interrogation of protein dynamics upon membrane binding and recruitment. This review will highlight the theory and development of HDX-MS and its application to examine the molecular basis of lipid signalling enzymes, specifically the regulation and activation of phosphoinositide 3-kinases (PI3Ks).

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Integration of G Protein α (Gα) Signaling by the Regulator of G Protein Signaling 14 (RGS14)

Cited by 31 publications

References 53 publications

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

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

Probing the dynamic regulation of peripheral membrane proteins using hydrogen deuterium exchange–MS (HDX–MS)

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