Arrestin-mediated signaling: Is there a controversy?

Gurevich, Vsevolod V.; Gurevich, Eugenia V.

doi:10.4331/wjbc.v9.i3.25

Cited by 46 publications

(39 citation statements)

References 91 publications

(139 reference statements)

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“…Histamineinduced up-regulation of H1R expression could be one of the outcomes of this nuclear ERK1/2 activity (Mizuguchi et al 2011). Total dependence of ERK1/2 activation on G protein has recently been reported for a panel of GPCRs belonging to different G protein-coupling groups (Alvarez-Curto et al 2016, Grundmann et al 2018, see also Gurevich & Gurevich 2018).…”

Section: Discussionmentioning

confidence: 94%

Seeing β-arrestin in action: The role of β-arrestins in Histamine 1 Receptor signaling

Pietraszewska-Bogiel

Goedhart

2019

Preprint

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ß-arrestins regulate G protein-coupled receptor functions by influencing their signaling activity and intracellular location. Histamine is a major chemical mediator of allergic reactions, and its action is mainly mediated by the G q/11 -and G i -coupled H1R.Contrary to accumulating insights into G protein-mediated signaling downstream of H1R, very little is known about the function of ß-arrestins in H1R signaling. Here, we describe dynamic, live cell measurements of ß-arrestin recruitment upon H1R activation in HEK293TN cells. Our observations classify H1R as a class A receptor, undergoing transient interactions with ß-arrestin. To investigate the relative contributions of G proteins and ß-arrestins to H1R signaling, we use specific G protein inhibitors, as well as ß-arrestin overexpression and depletion, and quantify various signaling outcomes in a panel of dynamic, live cell biosensor assays. Overall, we link ß-arrestins to desensitization of H1R-mediated signaling and show that ERK activation downstream of endogenous (HeLa, HUVEC) or transiently expressed (HEK293TN) H1R is largely G q -mediated.

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Section: Discussionmentioning

confidence: 94%

Seeing β-arrestin in action: The role of β-arrestins in Histamine 1 Receptor signaling

Pietraszewska-Bogiel

Goedhart

2019

Preprint

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“…The C-terminal extension is also the largest part of the protein facing the cytosol, the N-terminus being periplasmic [19]. Mep2 cytosolic domains are likely to interact with signaling partners in analogy to 7TM GPCRs that are widely appreciated to act as platforms coordinating interactions of proteins involved in a variety of aspects of cell signaling [49]. A close link was observed between the efficiency of filamentation induction and the substrate transport efficiency of Mep2 that impacts on the consequent growth ability at limiting ammonium levels.…”

Section: Discussionmentioning

confidence: 99%

Yeast filamentation signaling is connected to a specific substrate translocation mechanism of the Mep2 transceptor

et al. 2020

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The dimorphic transition from the yeast to the filamentous form of growth allows cells to explore their environment for more suitable niches and is often crucial for the virulence of pathogenic fungi. In contrast to their Mep1/3 paralogues, fungal Mep2-type ammonium transport proteins of the conserved Mep-Amt-Rh family have been assigned an additional receptor role required to trigger the filamentation signal in response to ammonium scarcity. Here, genetic, kinetic and structure-function analyses were used to shed light on the poorly characterized signaling role of Saccharomyces cerevisiae Mep2. We show that Mep2 variants lacking the C-terminal tail conserve the ability to induce filamentation, revealing that signaling can proceed in the absence of exclusive binding of a putative partner to the largest cytosolic domain of the protein. Our data support that filamentation signaling requires the conformational changes accompanying substrate translocation through the pore crossing the hydrophobic core of Mep2. pHluorin reporter assays show that the transport activity of Mep2 and of non-signaling Mep1 differently affect yeast cytosolic pH in vivo, and that the unique pore variant Mep2 H194E , with apparent uncoupling of transport and signaling functions, acquires increased ability of acidification. Functional characterization in Xenopus oocytes reveals that Mep2 mediates electroneutral substrate translocation while Mep1 performs electrogenic transport. Our findings highlight that the Mep2-dependent filamentation induction is connected to its specific transport mechanism, suggesting a role of pH in signal mediation. Finally, we show that the signaling process is conserved for the Mep2 protein from the human pathogen Candida albicans.

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“…There are also numerous studies suggesting a specific role for the nonvisual arrestins in receptor-independent activation of ERK1/2, AKT, JNK3, and NF-kB (6,(22)(23)(24)(25)(26). Complexity of the signaling process is further increased by cross-talk between the signaling pathways initiated by G proteins and arrestins (27). When one considers the sheer number of receptors, ligands, effectors, and alternative pathway connections, it is not surprising that the best efforts of the field have not yet been able to identify how an extracellular stimulus, be it hormonal or sensory, directs signaling toward the correct biological response.The complexity of GPCR signaling is well exemplified by the five dopamine receptors (D1R -D5R).…”

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confidence: 99%

“…Although these are well-studied effectors, there is an intense debate in the field as to how activated dopamine receptor selects between these pathways, and even debate as to whether G proteins or arrestins are the primary intermediary (30,(45)(46)(47)(48). In general, the role of arrestins and G proteins must be experimentally studied in each case, and the answers are likely to be different (22,27,49) Here, we used the D1R as a model receptor to explore global questions about the mechanisms of GPCR signal bias using ERK1/2 and Src kinase as model effectors. We first determined which aspects of dopaminedependent ERK1/2 and Src signaling were mediated by arrestin versus G proteins.…”

mentioning

confidence: 99%

Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor

Kaya

Perry

Gurevich

et al. 2020

Preprint

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Agonist-activated G protein-coupled receptors (GPCRs) must correctly select from hundreds of potential downstream signaling cascades and effectors. To accomplish this, GPCRs first bind to an intermediary signaling protein, such as G protein or arrestin. These intermediaries initiate signaling cascades that promote the activity of different effectors, including several protein kinases. The relative roles of G proteins versus arrestins in initiating and directing signaling is hotly debated, and it remains unclear how the correct final signaling pathway is chosen given the ready availability of protein partners. Here, we begin to deconvolute the process of signal bias from the dopamine D1 receptor (D1R) by exploring factors that promote the activation of ERK1/2 or Src, the kinases that lead to cell growth and proliferation. We found that ERK1/2 activation involves both arrestin and Gas, while Src activation depends solely on arrestin. Interestingly, we found that the phosphorylation pattern influences both arrestin and Gas coupling, suggesting an additional way the cells regulate G protein signaling. The phosphorylation sites in the D1R intracellular loop 3 are particularly important for directing the binding of G protein versus arrestin and for selecting between the activation of ERK1/2 and Src. Collectively, these studies correlate functional outcomes with a physical basis for signaling bias and provide fundamental information on how GPCR signaling is directed. Significance Statement:The functional importance of receptor phosphorylation in GPCR regulation has been demonstrated. Over the past decade, the phospho-barcode concept was developed to explain the multidimensional nature of the arrestin-dependent signaling network downstream of GPCRs. Here, we used the dopamine-1 receptor (D1R) to explore the effect of receptor phosphorylation on G protein-dependent and arrestin-dependent ERK and Src activation. Our studies suggest that D1R intracellular loop-3 phosphorylation affects both G proteins and arrestins. Differential D1R phosphorylation can direct signaling toward ERK or Src activation. This implies that phosphorylation induces different conformations of receptor and/or bound arrestin to initiate or select different cellular signaling pathways. \body Although it is tempting to divide GPCR signaling into these two branches, G protein-dependent and arrestindependent, the nature of signaling in the cell is much more complex (reviewed in (1, 7, 8)). As a result, this classical paradigm does not fully explain the range of biological responses observed when a GPCR is activated. For example, agonist identity can affect the recruitment of different G-proteins or arrestins, which determines the selection of downstream effectors (9). In addition, some activated GPCRs may interact directly with non-canonical signaling partners, including Src-family kinases (10-21). There are also numerous studies suggesting a specific role for the nonvisual arrestins in receptor-independent activation of ERK1/2, AKT, JNK3, and NF-kB (6,(22...

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Arrestin-mediated signaling: Is there a controversy?

Cited by 46 publications

References 91 publications

Seeing β-arrestin in action: The role of β-arrestins in Histamine 1 Receptor signaling

Seeing β-arrestin in action: The role of β-arrestins in Histamine 1 Receptor signaling

Yeast filamentation signaling is connected to a specific substrate translocation mechanism of the Mep2 transceptor

Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor

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