G Protein–Coupled Receptor Signaling Through β-Arrestin–Dependent Mechanisms

Jean-Charles, Pierre-Yves; Kaur, Suneet; Shenoy, Sudha K.

doi:10.1097/fjc.0000000000000482

Cited by 172 publications

(121 citation statements)

References 212 publications

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“…When bound to an agonist-activated GPCR arrestins block access of G proteins to the receptor. In recent years much broader roles of arrestins have been uncovered in which they may initiate signal transduction events distinct from, and apparently not dependent upon, G protein activation [42,43,44]. Understanding the contributions and roles of arrestin-2 and arrestin-3 as initiators of signal transduction via distinct pathways is at the heart of the push to identify 'bias' ligands that may lead to the development of improved therapeutics [41,42,43].…”

Section: Elimination Of Arrestinsmentioning

confidence: 99%

Genome Editing Provides New Insights into Receptor-Controlled Signalling Pathways

Milligan

Inoue

2018

Trends in Pharmacological Sciences

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Rapid developments in genome editing, based largely on CRISPR/Cas9 technologies, are offering unprecedented opportunities to eliminate the expression of single or multiple gene products in intact organisms and in model cell systems. Elimination of individual G protein-coupled receptors (GPCRs), both single and multiple G protein subunits, and arrestin adaptor proteins is providing new and sometimes unanticipated insights into molecular details of the regulation of cell signalling pathways and the behaviour of receptor ligands. Genome editing is certain to become a central component of therapeutic target validation, and will provide pharmacologists with new understanding of the complexities of action of novel and previously studied ligands, as well as of the transmission of signals from individual cell-surface receptors to intracellular signalling cascades.

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Section: Elimination Of Arrestinsmentioning

confidence: 99%

Genome Editing Provides New Insights into Receptor-Controlled Signalling Pathways

Milligan

Inoue

2018

Trends in Pharmacological Sciences

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“…Activated ␤ 1 AR and ␤ 2 AR are regulated via phosphorylation by GPCR kinases (GRKs) and binding of the multifunctional adaptor proteins called ␤-arrestins, which precede receptor endocytosis and post-endocytic sorting (1,9). ␤ 1 AR signaling is significantly attenuated in failing hearts due to receptor desensitization and down-regulation (10,11).…”

mentioning

confidence: 99%

The deubiquitinase ubiquitin–specific protease 20 is a positive modulator of myocardial β1-adrenergic receptor expression and signaling

Yu¹,

Jean-Charles²,

Abraham

et al. 2019

Journal of Biological Chemistry

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Reversible ubiquitination of G protein-coupled receptors regulates their trafficking and signaling; whether deubiquitinases regulate myocardial ␤ 1 -adrenergic receptors (␤ 1 ARs) is unknown.Wereportthatubiquitin-specificprotease20(USP20)deubiquitinates and attenuates lysosomal trafficking of the ␤ 1 AR. ␤ 1 AR-induced phosphorylation of USP20 Ser-333 by protein kinase A-␣ (PKA␣) was required for optimal USP20-mediated regulation of ␤ 1 AR lysosomal trafficking. Both phosphomimetic (S333D) and phosphorylation-impaired (S333A) USP20 possess intrinsic deubiquitinase activity equivalent to WT activity. However, unlike USP20 WT and S333D, the S333A mutant associated poorly with the ␤ 1 AR and failed to deubiquitinate the ␤ 1 AR. USP20 -KO mice showed normal baseline systolic function but impaired ␤ 1 AR-induced contractility and relaxation. Dobutamine stimulation did not increase cAMP in USP20 -KO left ventricles (LVs), whereas NKH477-induced adenylyl cyclase activity was equivalent to WT. The USP20 homolog USP33, which shares redundant roles with USP20, had no effect on ␤ 1 AR ubiquitination, but USP33 was up-regulated in USP20 -KO hearts suggesting compensatory regulation. Myocardial ␤ 1 AR expression in USP20 -KO was drastically reduced, whereas ␤ 2 AR expression was maintained as determined by radioligand binding in LV sarcolemmal membranes. Phospho-USP20 was significantly increased in LVs of wildtype (WT) mice after a 1-week catecholamine infusion and a 2-week chronic pressure overload induced by transverse aortic constriction (TAC). Phospho-USP20 was undetectable in ␤ 1 AR KO mice subjected to TAC, suggesting a role for USP20 phosphorylation in cardiac response to pressure overload. We conclude that USP20 regulates ␤ 1 AR signaling in vitro and in vivo. Additionally, ␤ 1 AR-induced USP20 phosphorylation may serve as a feedforward mechanism to stabilize ␤ 1 AR expression and signaling during pathological insults to the myocardium. by guest on July 10, 2020 http://www.jbc.org/ Downloaded from Figure 1. Agonist-induced ubiquitination and lysosomal trafficking of the ␤ 1 AR.A, HEK-293 cells stably transfected with FLAG-␤ 1 AR were stimulated with 1 M isoproterenol (Iso) for indicated times and subjected to FLAG IP followed by serial immunoblotting (IB) with anti-ubiquitin antibody (rabbit polyclonal, Bethyl Laboratories Inc.) and polyclonal FLAG antibody. The 1st lane shows the background signal obtained from HEK-293 cells transfected with vector. B, ubiquitin smears were quantitated and normalized to cognate FLAG-␤ 1 AR bands and plotted as % maximum signal (see "Experimental procedures"). The graph includes means Ϯ S.E. from four independent experiments. *, p Ͻ 0.05 compared with 0 min, one-way ANOVA, and Bonferroni's test. C, HEK-293 cells with stable transfection of ␤ 1 AR-CFP were stimulated with 1 M Iso for the indicated times, and the distribution of ␤ 1 AR (red) and LAMP1 (green) was visualized with LSM-510 confocal microscope. Representative images are shown, and quantification of colocalization from Ն13 z...

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“…EPCR acts as a switch for the bidirectional activities of PAR1 [8]. EPCR-dependent cytoprotective signaling is mediated by PAR1 phosphorylation by GRK5 through beta-arrestin, resulting in reduced endothelial permeability due to Rac1 activation [16,19]. The contribution of Gai to these reactions is not well understood, however.…”

Section: Bidirectional Activities Of Thrombinmentioning

confidence: 99%

“…Different Gproteins recognize their own specific effectors, resulting in a variety of possible signaling pathways via one GPCR. Additionally, signaling via phosphorylated GPCRs is mediated via beta-arrestin instead of Gproteins, although details of the signaling mechanism remain unclear [16]. Some receptor cofactors appear to play significant roles in signal transduction, however.…”

Section: Thrombin Signaling Via Parsmentioning

confidence: 99%

Bidirectional Pathologic Effects of Thrombin

Hidai¹

2018

Anat Physiol

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Hemostasis is an essential reaction in organisms with circulatory systems. To stop bleeding as soon as possible, reactions of the coagulation system proceed rapidly and are regulated by positive feedback loops. However, coagulation can be harmful when induced at inappropriate sites, potentially resulting in local thromboembolisms in vital organs such as the heart and brain and systemic microthrombi in conditions such as disseminated intravascular coagulopathy. Increasingly, reports indicate that coagulation-related factors can cause serious diseases without obvious thromboembolism-associated ischemia, for example, atherosclerosis and Alzheimer disease. Thrombin is an essential coagulation factor that can also cause tissue injury, particular to endothelial cells. However, thrombin can also function as a tissue-protective factor depending on conditions. Endothelial protein C receptor (EPCR) and protease-activated receptors (PARs) regulate thrombin activity, but many details regarding the mechanisms remain unknown. This short review summarizes the bidirectional effects of thrombin signaling via EPCR and PAR1 and discusses points relevant to translating the tissue-protective effects of thrombin into clinical benefits.

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G Protein–Coupled Receptor Signaling Through β-Arrestin–Dependent Mechanisms

Cited by 172 publications

References 212 publications

Genome Editing Provides New Insights into Receptor-Controlled Signalling Pathways

Genome Editing Provides New Insights into Receptor-Controlled Signalling Pathways

The deubiquitinase ubiquitin–specific protease 20 is a positive modulator of myocardial β1-adrenergic receptor expression and signaling

Bidirectional Pathologic Effects of Thrombin

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