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Delineation of a conserved arrestin-biased signaling repertoire in vivo

ABSTRACT: Biased G protein-coupled receptor agonists engender a restricted repertoire of downstream events from their cognate receptors, permitting them to produce mixed agonist-antagonist effects in vivo. While this opens the possibility of novel therapeutics, it complicates rational drug design, since the in vivo response to a biased agonist cannot be reliably predicted from its in vitro efficacy. We have employed novel informatic approaches to characterize the in vivo transcriptomic signature of the arrestin pathway-selective parathyroid hormone analog [D-Trp12, Tyr34]-bPTH(7-34) in six different murine tissues after chronic drug exposure. We find that [D-Trp12, Tyr34]-bPTH(7-34) elicits a distinctive arrestin-signaling focused transcriptomic response that is more coherently regulated across tissues than that of the pluripotent agonist, hPTH(1-34). This arrestin-focused network is closely associated with transcriptional control of cell growth and development. Our demonstration of a conserved arrestin-dependent transcriptomic signature suggests a framework within which the in vivo outcomes of arrestin-biased signaling may be generalized.

ORGANISM(S): Mus musculus

PROVIDER: GSE64485 | GEO | 2015/03/05

SECONDARY ACCESSION(S): PRJNA271097

REPOSITORIES: GEO

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beta-Arrestin Pathway-Selective G Protein-Coupled Receptor Agonists Engender Unique Biological Efficacy In Vivo

Project description:Biased GPCR agonists are orthosteric ligands that possess pathway-selective efficacy, activating or inhibiting only a subset of the signaling repertoire of their cognate receptors. In vitro, D-Trp12,Tyr34-bPTH(7-34) (PTH-{beta}arr), a biased agonist for the type 1 parathyroid hormone receptor, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, both PTH-{beta}arr and the conventional agonist PTH(1-34) stimulate anabolic bone formation. To understand how two PTH1R ligands with markedly different in vitro efficacy could elicit similar in vivo responses, we analyzed transcriptional profiles from calvarial bone of mice treated for 8 weeks with vehicle, PTH-{beta}arr or PTH(1-34). Treatment of wild type mice with PTH-{beta}arr primarily affected pathways that promote expansion of the osteoblast pool, notably cell cycle regulation, cell survival and migration. These responses were absent in beta-arrestin2 null mice, identifying them as downstream targets of beta-arrestin2-mediated signaling. In contrast, PTH(1-34) primarily affected pathways classically associated with enhanced bone formation, including collagen synthesis and matrix mineralization. PTH(1-34) actions were less dependent on beta-arrestin2, as might be expected of a ligand capable of G protein activation. These results illustrate the uniqueness of biased agonism in vivo and demonstrate that functional selectivity can be exploited to change the quality of GPCR efficacy.

2013-03-07 | GSE35181 | GEO

Lung transcriptomes of wild type, β-arrestin 1 -/-, and β-arrestin 2 -/- mice exposed to normoxia or chronic hypoxia

Project description:We found that β-arrestin 1 -/- mice were more sensitive to hypoxia-induced pulmonary arterial hypertension with increased right ventricle hypertrophy and higher right ventricle systolic pressure, while β-arrestin 2 -/- mice developed right ventricle hypertrophy comparable to wild type mice. Moreover, β-arrestin 1 -/- mice had worse right ventricle function than wild type mice in response to chronic hypoxia, whereas β-arrestin 2 -/- mice relatively preserved right ventricle function compared to wild type mice. To investigate the molecular mechanisms responsible for the worse PAH in β-arrestin 1 -/- mice, we performed lung transcriptome analysis of wild type, β-arrestin 1 -/-, and β-arrestin 2 -/- mice using high-throughput RNA-seq.

2018-11-19 | GSE110131 | GEO

Mapping AT1R biased signaling using proximity-labeling and proteomics identifies diverse actions of biased agonists

Project description:Angiotensin II type 1 receptors (AT1Rs) are one of the most widely studied G protein-coupled receptors. To fully appreciate the diversity in cellular signaling profiles activated by AT1R transducer-biased ligands, we utilized peroxidase-catalyzed proximity labeling to capture proteins in close proximity to AT1Rs in response to six different ligands: Angiotensin II (full agonist), S1I8 (partial agonist), TRV055 and TRV056 (G protein-biased agonists), TRV026 and TRV027 (β-arrestin biased agonists) at 90s, 10min, and 60min after stimulation. We systematically analyzed the kinetics of AT1R trafficking and determined that distinct ligands lead AT1R to different cellular compartments for downstream signaling activation and receptor degradation/recycling. Distinct proximity labelling of proteins from a number of functional classes, including GTPases, adaptor proteins, and kinases were activated by different ligands suggesting unique signaling and physiological roles of the AT1R. Ligands within the same class, i.e. either G protein-biased or -arrestin-biased, shared high similarity in their labelling profiles. Comparison between ligand classes revealed distinct signaling activation such as greater labeling by G protein biased ligands on ESCRT-0 complex proteins that act as sorting machinery for ubiquitinated proteins. Our study provides a comprehensive analysis of AT1R receptor trafficking kinetics and signaling activation profiles induced by distinct classes of ligands.

2021-03-25 | PXD023814 | Pride

Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors

Project description:G protein-coupled receptors (GPCRs) are typically characterized by their seven transmembrane (7TM) architecture, and interaction with two universal signal-transducers namely, the heterotrimeric G-proteins and β-arrestins (βarrs). Synthetic ligands and receptor mutants have been designed to elicit transducer-coupling preferences and distinct downstream signaling outcomes for many GPCRs. This raises the question if some naturally-occurring 7TMRs may selectively engage one of these two signal-transducers, even in response to their endogenous agonists. Although there are scattered hints in the literature that some 7TMRs lack G-protein coupling but interact with βarrs, an in-depth understanding of their transducer-coupling preference, GRK-engagement, downstream signaling and structural mechanism remains elusive. Here, we use an array of cellular, biochemical and structural approaches to comprehensively characterize two non-canonical 7TMRs namely, the human decoy D6 receptor (D6R) and the human complement C5a receptor (C5aR2), in parallel with their canonical GPCR counterparts, CCR2 and C5aR1, respectively. We discover that D6R and C5aR2 couple exclusively to βarrs, exhibit distinct GRK-preference, and activate non-canonical downstream signaling partners. We also observe that βarrs, in complex with these receptors, adopt distinct conformations compared to their canonical GPCR counterparts despite being activated by a common natural agonist. Our study therefore establishes D6R and C5aR2 as bona-fide arrestin-coupled receptors (ACRs), and provides important insights into their regulation by GRKs and downstream signaling with direct implications for biased agonism.

2021-11-03 | PXD027887 | Pride

β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

Project description:Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that β-arrestin 2 also promotes virus-induced production of IFN-β and clearance of viruses in macrophages. β-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstreatm stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of β-arrestin 2 at Lys171 facilitates the activation of the cGAS–STING signaling and the production of IFN-β. In vitro, viral infection induces the degradation of β-arrestin 2 to facilitate immune evasion, while a β-blocker, carvedilol, rescues β-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of β-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.

2020-10-22 | GSE159735 | GEO

Mus musculus

Project description:Delineation of a conserved arrestin-biased signaling repertoire in vivo

| PRJNA271097 | ENA

Exploring GPCR-arrestin interfaces with genetically encoded crosslinkers

Project description:-arrestins (arr1 and arr2) are ubiquitous regulators of G protein-coupled receptor (GPCR) signalling. Available data suggest that -arrestins dock to different receptors in different ways. However, the structural characterization of arrestin-GPCR complexes is challenging and alternative approaches to study arrestin-GPCR complexes are needed. Here, starting from the finger loop as a major site for the interaction of arrestins with GPCRs, we genetically incorporate non-canonical amino acids for photo- and chemical crosslinking into arr1 and arr2 and explore binding topologies to GPCRs forming either stable or transient complexes with arrestin: the vasopressin receptor 2 (rhodopsin-like), the corticotropin releasing factor receptor 1 and the parathyroid hormone receptor 1 (both secretin-like). We show that each receptor leaves a unique footprint on arrestin, whereas the two -arrestins yield quite similar crosslinking patterns. Furthermore, we show that the method allows defining the orientation of arrestin respect to the GPCR. Finally, we provide direct evidence for the formation of arrestin oligomers in the cell.

2020-09-21 | PXD020418 | Pride

Impact of beta-arrestin-2 deficiency on intestinal tumorigenesis in Apc-mutated mice

Project description:This SuperSeries is composed of the following subset Series: GSE24575: Beta-arrestin-2 deficiency effect on intestinal tumorigenesis in Apc-mutated mice GSE24576: Gene expression analysis of tumors from ApcD14/+ mice Refer to individual Series

2012-01-20 | E-GEOD-24577 | biostudies-arrayexpress

GRK2/3-regulated, but not constitutive, phosphorylation of the G protein-coupled receptor GPR84 controls arrestin interactions and subsequent function

Project description:Although the GPR84 activators 2-HTP and 6-OAU promoted phosphorylation of human GPR84 and its interactions with arrestin-3, PSB-16671 and DL-175 did not. Replacement of all 21 serine and threonine residues within the third intracellular loop, but not the 2 serines in the C-terminal tail, eliminated incorporation of [32P] promoted by 2-HTP and greatly reduced receptor-arrestin-3 interactions. Mass spectrometry indicated that GPR84 was phosphorylated constitutively on residues Ser221 and Ser224 whilst a range of sites became phosphorylated in response to 2-HTP. An antiserum able to identify pSer221/pSer224 recognised GPR84 from cells treated both with and without 2-THP, whilst an antiserum able to identify pThr263/pThr264 recognised GPR84 only after exposure to 2-HTP. Treatment with neither PSB-16671 nor DL-175 was able to promote receptor recognition by this antiserum. 2-HTP-mediated phosphorylation of Thr263/Thr264 was prevented by two chemically distinct GPR84 antagonists but neither affected constitutive phosphorylation of Ser221/Ser224. 2-HTP-mediated phosphorylation of Thr263/Thr264 but not constitutive phosphorylation of Ser221/Ser224 was prevented by GRK2/3 inhibition. Mutation of residues Thr263 and Thr264 to alanine generated a variant of GPR84 as limited in 2-HTP-induced interactions with arrestin-3 as when all 21 serine and threonine were eliminated from the third intracellular loop. By contrast this mutant was unaffected in capacity to reduce cAMP levels in response to 2-HTP. Homology modelling and mutagenesis provided molecular insight into differences in agonist function. These studies define key residues, regulated by GRK2/3, that define effective interactions with arrestins and provide novel tools to monitor the phosphorylation and functional status of GPR84.

2022-06-09 | PXD031252 | Pride

Differentiation Time Course Analysis of Gene Expression in Primary Osteoblasts from Wild Type and β-Arrestin 2 Knockout Mice

Project description:Gene expression analysis was performed on differentiating obsteoblasts isolated from calvaria of C57BL/6J wildtype or B-arrestin 2 knockout mice.

2022-08-16 | GSE181459 | GEO

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