Lack of beta-arrestin signaling in the absence of active G proteins

Grundmann, Manuel; Merten, Nicole; Malfacini, Davide; Inoue, Asuka; Preis, Philip; Simon, Katharina; Rüttiger, Nelly; Ziegler, Nicole; Benkel, Tobias; Schmitt, Nina; Ishida, S.; Müller, Ines; Reher, Raphael; Kawakami, Kouki; Inoue, Akihiro; Rick, Ulrike; Kühl, Toni; Imhof, Diana; Aoki, Junken; König, Gabriele M.; Hoffmann, Carsten; Gomeza, Jesús; Wess, Jürgen; Kostenis, Evi

doi:10.1038/s41467-017-02661-3

Cited by 307 publications

(296 citation statements)

References 68 publications

Supporting

Mentioning

265

Contrasting

Unclassified

Order By: Relevance

“…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%

“…However, insight in the dependence of this recruitment on phosphorylation requires additional experiments. ß-arrestins constitute important regulators of GPCR function, whose central role is to desensitize G protein-mediated signaling (Alvarez-Curto et al 2016, Grundmann et al 2018, Luttrell et al 2018, reviewed in Gurevich & Gurevich 2019. At the same time, ß-arrestins can scaffold various downstream effectors and were shown to have a stimulatory effect on the selected aspects of GPCR signaling (Jean-Charles et al 2017, Grundmann et al 2018.…”

Section: Discussionmentioning

confidence: 99%

“…ß-arrestins constitute important regulators of GPCR function, whose central role is to desensitize G protein-mediated signaling (Alvarez-Curto et al 2016, Grundmann et al 2018, Luttrell et al 2018, reviewed in Gurevich & Gurevich 2019. At the same time, ß-arrestins can scaffold various downstream effectors and were shown to have a stimulatory effect on the selected aspects of GPCR signaling (Jean-Charles et al 2017, Grundmann et al 2018. To investigate this (putatively) complex ß-arrestin role in H1R-mediated signaling, we implemented both ß-arrestin overexpression and knockdown strategies to study their effect on three different signaling outcomes of H1R activation, i.e.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Pietraszewska-Bogiel

Goedhart

2019

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Pietraszewska-Bogiel

Goedhart

2019

Preprint

View full text Add to dashboard Cite

show abstract

“…There is particularly strong evidence that the pro-proliferation extracellular signalregulated kinases 1/2 (ERK1/2) (41-43) and Src kinase (44) are among the key effectors regulated by dopamine signaling. 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.…”

mentioning

confidence: 99%

Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor

Kaya

Perry

Gurevich

et al. 2020

Preprint

View full text Add to dashboard Cite

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...

show abstract

“…Although arrestin-dependent signaling was long considered to be G protein independent, 30 recent studies showed that arrestin-mediated signaling in many cases (possibly always, although generalizations are dangerous) depends on the activation of G proteins. 73,74 In fact, this is biologically understandable, as the previous model of arrestin-dependent signaling did not explain how the upstream-most kinases, such as c-Raf1 in case of ERK1/2, or ASK1 in case of JNK3, were activated. These kinases are not activated by arrestin-dependent scaffolding and must come to the scaffold already active.…”

Section: Channeling the Signaling Toward Or Away From Selected Pathwaysmentioning

confidence: 88%

Arrestins: Introducing Signaling Bias Into Multifunctional Proteins

Gurevich

Chen

Gurevich

2018

Progress in Molecular Biology and Translational Science

View full text Add to dashboard Cite

Arrestins were discovered as proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) and block their interactions with G proteins, i.e., for their role in homologous desensitization of GPCRs. Mammals express only four arrestin subtypes, two of which are largely restricted to the retina. Two nonvisual arrestins are ubiquitous and interact with hundreds of different GPCRs and dozens of other binding partners. Changes of just a few residues on the receptor-binding surface were shown to dramatically affect GPCR preference of inherently promiscuous nonvisual arrestins. Mutations on the cytosol-facing side of arrestins modulate their interactions with individual downstream signaling molecules. Thus, it appears feasible to construct arrestin mutants specifically linking particular GPCRs with signaling pathways of choice or mutants that sever the links between selected GPCRs and unwanted pathways. Signaling-biased “designer arrestins” have the potential to become valuable molecular tools for research and therapy.

show abstract

Lack of beta-arrestin signaling in the absence of active G proteins

Cited by 307 publications

References 68 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

Phosphorylation barcode-dependent signal bias of the dopamine D1 receptor

Arrestins: Introducing Signaling Bias Into Multifunctional Proteins

Contact Info

Product

Resources

About