xRic‐8 is a GEF for Gsα and participates in maintaining meiotic arrest in <i>Xenopus laevis</i> oocytes

Romo, Ximena; Pastén, Pamela; Martinez, Silvana; Soto, Ximena; Lara, Pablo; Arellano, Antonieta Ramirez de; Torrejón, Marcela; Montecino, Martín; Hinrichs, María Victoria; Olate, Juan

doi:10.1002/jcp.21257

Cited by 24 publications

(18 citation statements)

References 34 publications

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“…Ric-8 proteins also preferentially bind wild-type or GDP-bound Ga subunits over constitutively active mutant (e.g., Gai 1 Q204L) or GTP-bound Ga subunits, prompting investigation of Ric-8 influence on G protein guanine nucleotide-cycle kinetics. Purified Ric-8A, Ric-8B, and Ric-8 proteins from multiple organisms exhibited in vitro guanine nucleotide exchange stimulatory activity (GEF) for subsets of Ga subunits (Tall et al, 2003;Afshar et al, 2004;Romo et al, 2008;Chan et al, 2011b;Wright et al, 2011;Kataria et al, 2013). The idea that Ric-8 might activate G proteins in cells as a non-GPCR GEF was logically consistent with the C. elegans genetic studies that showed ric-8 mutant negative influence of G protein signaling.…”

Section: Introductionsupporting

confidence: 54%

“…Demonstration of direct binding between Ga subunits and mammalian Ric-8A or Ric-8B proteins was made from yeast two-hybrid (Y2H) screens and protein pull-down experiments (Klattenhoff et al, 2003;Tall et al, 2003). Single-copy ancestral Ric-8 binds all Ga subunits present in these organisms, whereas mammalian Ric-8A binds the Gai/o, Ga12/13, and Gaq/11 classes, and Ric-8B has exclusive preference for the Gas/olf-class (Tall et al, 2003;Matsuzaki, 2005;Von Dannecker et al, 2005;Romo et al, 2008;Chan et al, 2011b). Ric-8 proteins also preferentially bind wild-type or GDP-bound Ga subunits over constitutively active mutant (e.g., Gai 1 Q204L) or GTP-bound Ga subunits, prompting investigation of Ric-8 influence on G protein guanine nucleotide-cycle kinetics.…”

Section: Introductionmentioning

confidence: 99%

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The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target

2014

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Resistance to inhibitors of cholinesterase (Ric-8)A and Ric-8B are essential genes that encode positive regulators of heterotrimeric G protein a subunits. Controversy persists surrounding the precise way(s) that Ric-8 proteins affect G protein biology and signaling. Ric-8 proteins chaperone nucleotide-free Ga-subunit states during biosynthetic protein folding prior to G protein heterotrimer assembly. In organisms spanning the evolutionary window of Ric-8 expression, experimental perturbation of Ric-8 genes results in reduced functional abundances of G proteins because G protein a subunits are misfolded and degraded rapidly. Ric-8 proteins also act as Ga-subunit guanine nucleotide exchange factors (GEFs) in vitro. However, Ric-8 GEF activity could strictly be an in vitro phenomenon stemming from the ability of Ric-8 to induce partial Ga unfolding, thereby enhancing GDP release. Ric-8 GEF activity clearly differs from the GEF activity of G protein-coupled receptors (GPCRs). G protein bg is inhibitory to Ric-8 action but obligate for receptors. It remains an open question whether Ric-8 has dual functions in cells and regulates G proteins as both a molecular chaperone and GEF. Clearly, Ric-8 has a profound influence on heterotrimeric G protein function. For this reason, we propose that Ric-8 proteins are as yet untested therapeutic targets in which pharmacological inhibition of the Ric-8/Ga protein-protein interface could serve to attenuate the effects of disease-causing G proteins (constitutively active mutants) and/or GPCR signaling. This minireview will chronicle the understanding of Ric-8 function, provide a comparative discussion of the Ric-8 molecular chaperoning and GEF activities, and support the case for why Ric-8 proteins should be considered potential targets for development of new therapies.

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Section: Introductionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target

2014

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“…This is the first time that an interaction between small molecules and G proteins has been shown to stimulate G proteins. Until now, proteins have only been known to act as GEFs (Guanine nucleotide Exchange Factors) on heterotrimeric G proteins (for example, RIC-8B is a GEF for Gs) [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

The action of ethanol on G protein. <i>In silico</i> and cellular/molecular evidences

Fernández¹,

Moreno²,

Barrientos³

et al. 2013

ABB

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Ethanol (EtOH) enhances glycinergic currents in the central nervous system (CNS). Because evidence for an interaction between the α1 subunit of the glycine receptor (α1GlyR) and the G protein Gβγ subunit exists in vitro and because cAMP levels are known to increase in response to EtOH, we wanted to investigate the interaction between Gβγ and α1GlyR in response to EtOH treatment in HEK293 cells and to explore the possible sites of interaction between EtOH and the Gαs subunit. His pull-down assays in GlyRHis6-transfected HEK293 cells incubated with ethanol or propofol revealed that only EtOH treatment increased the binding of Gβγ heterodimers to α1GlyR. Using molecular modelling (protein structure prediction), was modelled the hGαs protein for the first time and validated this model by site-directed mutagenesis. By molecular docking, we identified some potential regions of interaction between hGαs and EtOH that are located on the SIII and SI regions of the Gαs. Therefore, we conclude that ethanol increases the interaction between α1GlyR and Gβγ in HEK293 cells, an effect that might be attributed to the interaction between EtOH and hGαs, which consequently stimulates hGαs.

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“…To investigate the relative amounts of cAMP under our experimental conditions, we used the dual luciferase reporter assay system (Promega, Madison, WI) following the manufacturer's protocol (Romo et al, 2008). In brief, HEK293 cells were grown in 24-well plates (80% confluent) and transfected with the plasmids pCRE-Luc and pRL-SV40 for cAMP-dependent firefly and Renilla reniformis luciferase activity, respectively.…”

Section: Methodsmentioning

confidence: 99%

Activated G Protein α_sSubunits Increase the Ethanol Sensitivity of Human Glycine Receptors

Yévenes

Moraga-Cid²,

Romo³

et al. 2011

J Pharmacol Exp Ther

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It is well known that ethanol modulates the function of the Cys loop ligand-gated ion channels, which include the inhibitory glycine receptors (GlyRs). Previous studies have consistently shown that transmembrane and extracellular sites are essential for ethanol actions in GlyRs. In addition, recent evidence has shown that the ethanol modulation of GlyRs is also affected by G protein activation through G␤␥ subunits. However, more specific roles of G protein ␣ subunits on ethanol actions are unknown. Here, we show that the allosteric effect of ethanol on the human ␣ 1 GlyR is selectively enhanced by the expression of G␣ s Q-L. For example, constitutively active G␣ s , but not G␣ q or G␣ i , was able to displace the alcohol sensitivity of GlyRs toward low millimolar concentrations (17 Ϯ 4 versus 48 Ϯ 5% at 100 mM). Experiments under conditions that increased cAMP and protein kinase A (PKA)-mediated signaling, on the contrary, did not produce the same enhancement in sensitivity, suggesting that the G␣ s Q-L effect was not dependent on cAMP/PKAdependent signaling. On the other hand, the effect of G␣ s Q-L was blocked by a G␤␥ scavenger (9 Ϯ 3% of control). Furthermore, two mutant receptors previously shown to have impaired interactions with G␤␥ were not affected by G␣ s Q-L, suggesting that G␤␥ is needed for enhancing ethanol sensitivity. These results support the conclusion that activated G␣ s can facilitate the G␤␥ interaction with GlyRs in presence of ethanol, independent of increases in cAMP signaling. Thus, these data indicate that the activated form of G␣ s is able to positively influence the effect of ethanol on a type of inhibitory receptor important for motor control, pain, and respiration.

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xRic‐8 is a GEF for Gsα and participates in maintaining meiotic arrest in Xenopus laevis oocytes

Cited by 24 publications

References 34 publications

The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target

The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target

The action of ethanol on G protein. <i>In silico</i> and cellular/molecular evidences

Activated G Protein α_sSubunits Increase the Ethanol Sensitivity of Human Glycine Receptors

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xRic‐8 is a GEF for Gsα and participates in maintaining meiotic arrest in Xenopus laevis oocytes

Cited by 24 publications

References 34 publications

The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target

The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target

The action of ethanol on G protein. &lt;i&gt;In silico&lt;/i&gt; and cellular/molecular evidences

Activated G Protein αsSubunits Increase the Ethanol Sensitivity of Human Glycine Receptors

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Product

Resources

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The action of ethanol on G protein. <i>In silico</i> and cellular/molecular evidences

Activated G Protein α_sSubunits Increase the Ethanol Sensitivity of Human Glycine Receptors