Artykuły w czasopismach na temat „?-arrestin”
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1
Santini, F., R. B. Penn, A. W. Gagnon, J. L. Benovic i J. H. Keen. "Selective recruitment of arrestin-3 to clathrin coated pits upon stimulation of G protein-coupled receptors". Journal of Cell Science 113, nr 13 (1.07.2000): 2463–70. http://dx.doi.org/10.1242/jcs.113.13.2463.
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Non-visual arrestins (arrestin-2 and arrestin-3) play critical roles in the desensitization and internalization of many G protein-coupled receptors. In vitro experiments have shown that both non-visual arrestins bind with high and approximately comparable affinities to activated, phosphorylated forms of receptors. They also exhibit high affinity binding, again of comparable magnitude, to clathrin. Further, agonist-promoted internalization of many receptors has been found to be stimulated by exogenous over-expression of either arrestin2 or arrestin3. The existence of multiple arrestins raises the question whether stimulated receptors are selective for a specific endogenous arrestin under more physiological conditions. Here we address this question in RBL-2H3 cells, a cell line that expresses comparable levels of endogenous arrestin-2 and arrestin-3. When (beta)(2)-adrenergic receptors are stably expressed in these cells the receptors internalize efficiently following agonist stimulation. However, by immunofluorescence microscopy we determine that only arrestin-3, but not arrestin-2, is rapidly recruited to clathrin coated pits upon receptor stimulation. Similarly, in RBL-2H3 cells that stably express physiological levels of m1AChR, the addition of carbachol selectively induces the localization of arrestin-3, but not arrestin-2, to coated pits. Thus, this work demonstrates coupling of G protein-coupled receptors to a specific non-visual arrestin in an in vivo setting.
2
JAHNS, Roland, Franck BORGESE, Sabine LINDENTHAL, Annette STRAUB, René MOTAIS i Bruno FIÉVET. "Trout red blood cell arrestin (TRCarr), a novel member of the arrestin family: cloning, immunoprecipitation and expression of recombinant TRCarr". Biochemical Journal 316, nr 2 (1.06.1996): 497–506. http://dx.doi.org/10.1042/bj3160497.
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Arrestins are cytosolic proteins involved in the desensitization of G-protein-coupled receptors. We report the cloning of trout red blood cell arrestin which shows 76, 82 and 52% identity with bovine β-arrestin1, β-arrestin2 and retinal arrestin respectively. Antibodies were generated against the C-terminus of trout red blood cell arrestin. These antibodies detected arrestin in erythrocyte cytosol and were able to precipitate the native protein. The Na+/H+ antiporter of trout red blood cell is activated by β-adrenergic stimulation and is then desensitized whereas the transmembrane signalling pathway is not. To investigate the subcellular distribution of arrestin on β-adrenergic activation and desensitization of the antiporter, precipitation experiments were carried out on trout erythrocytes. A desensitization-dependent shift in cytosolic arrestin to the membranes could not be detected using the immunoprecipitation technique but we cannot exclude the possibility that a small number of cytosolic arrestins might be involved in the regulation of membrane proteins in trout erythrocyte. Recombinant trout arrestin was produced in a protease-deficient Escherichia coli strain and its functionality was tested in a reconstituted rhodopsin assay. The recombinant protein provides a suitable tool for investigating the target for arrestin in trout red blood cell, which still remains to be identified.
3
Rakib, Ahmed, Taslima Akter Eva, Saad Ahmed Sami, Saikat Mitra, Iqbal Hossain Nafiz, Ayan Das, Abu Montakim Tareq i in. "Beta-Arrestins in the Treatment of Heart Failure Related to Hypertension: A Comprehensive Review". Pharmaceutics 13, nr 6 (5.06.2021): 838. http://dx.doi.org/10.3390/pharmaceutics13060838.
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Heart failure (HF) is a complicated clinical syndrome that is considered an increasingly frequent reason for hospitalization, characterized by a complex therapeutic regimen, reduced quality of life, and high morbidity. Long-standing hypertension ultimately paves the way for HF. Recently, there have been improvements in the treatment of hypertension and overall management not limited to only conventional medications, but several novel pathways and their pharmacological alteration are also conducive to the treatment of hypertension. Beta-arrestin (β-arrestin), a protein responsible for beta-adrenergic receptors’ (β-AR) functioning and trafficking, has recently been discovered as a potential regulator in hypertension. β-arrestin isoforms, namely β-arrestin1 and β-arrestin2, mainly regulate cardiac function. However, there have been some controversies regarding the function of the two β-arrestins in hypertension regarding HF. In the present review, we try to figure out the paradox between the roles of two isoforms of β-arrestin in the treatment of HF.
4
Li, Dongjun, i Donna Woulfe. "Arrestin-2 Differentially Regulates PAR4 and P2Y12 Receptor Signaling in Platelets". Blood 112, nr 11 (16.11.2008): 110. http://dx.doi.org/10.1182/blood.v112.11.110.110.
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Abstract Arrestins play important roles in the function of G Protein-Coupled Receptors (GPCRs) in many cells, but their roles in platelets remain uncharacterized. While the classical role of arrestins is considered to be the internalization and desensitization of GPCRs, more recent studies suggest that arrestins can serve as molecular scaffolds to recruit phosphatidyl inositol-3 kinases (PI3Ks) to GPCRs and promote PI3K-dependent signaling. Due to the multifunctional role of arrestins, we sought to determine whether arrestins regulate Akt activation in platelets and thrombosis in living animals. Co-immunoprecipitation experiments indicate that arrestin-2 associates with PAR4 in thrombin-treated platelets and P2Y12 in ADP-treated platelets, but neither receptor in resting cells. Interestingly, association of arrestin-2 with PAR4 was also stimulated by ADP and PAR4-induced association of arrestin with PAR4 was inhibited by P2Y12 antagonists or apyrase. To determine the functional role of arrestin-2 in platelets, ADP- and thrombin receptor-stimulated Akt phosphorylation was compared in platelets from arrestin-2 knock-out versus WT mice. Akt phosphorylation stimulated by 0.8 mM AYPGKF PAR4 agonist peptide was reduced by an average of 77% in arrestin-2 knock-out platelets compared to WT controls (significantly different, p=0.007, n=3 in each group), but ADP-stimulated Akt phosphorylation was unaffected (p=.38, n=3 each). PAR4-stimulated fibrinogen binding was also reduced in arrestin2−/− platelets (by 58.5% in 1 mM AYPGKF-stimulated platelets compared to WT controls), whereas ADP-stimulated fibrinogen binding was not. Finally, arrestin2 knock-out mice were less sensitive to ferric chloride-induced thrombosis than WT mice: 55% of WT mice (n-=9) formed occlusive thrombi after 2min15sec exposure of the carotid artery to 10% ferric chloride, whereas only 11% of WT mice (n=9) formed occlusive thrombi under the same conditions. In conclusion, arrestin-2 associates with both PAR4 and P2Y12 receptors, but differentially regulates their signaling to Akt and fibrinogen binding and appears to play a net positive role in regulating thrombosis in vivo.
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Morris, Gavin E., Carl P. Nelson, Paul J. Brighton, Nicholas B. Standen, R. A. John Challiss i Jonathon M. Willets. "Arrestins 2 and 3 differentially regulate ETA and P2Y2 receptor-mediated cell signaling and migration in arterial smooth muscle". American Journal of Physiology-Cell Physiology 302, nr 5 (1.03.2012): C723—C734. http://dx.doi.org/10.1152/ajpcell.00202.2011.
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Overstimulation of endothelin type A (ETA) and nucleotide (P2Y) Gαq-coupled receptors in vascular smooth muscle causes vasoconstriction, hypertension, and, eventually, hypertrophy and vascular occlusion. G protein-coupled receptor kinases (GRKs) and arrestin proteins are sequentially recruited by agonist-occupied Gαq-coupled receptors to terminate phospholipase C signaling, preventing prolonged/inappropriate contractile signaling. However, these proteins also play roles in the regulation of several mitogen-activated protein kinase (MAPK) signaling cascades known to be essential for vascular remodeling. Here we investigated whether different arrestin isoforms regulate endothelin and nucleotide receptor MAPK signaling in rat aortic smooth muscle cells (ASMCs). When intracellular Ca2+ levels were assessed in isolated ASMCs loaded with Ca2+-sensitive dyes, P2Y2 and ETA receptor desensitization was attenuated by selective small-interfering (si)RNA-mediated depletion of G protein-coupled receptor kinase 2 (GRK2). Using similar siRNA techniques, knockdown of arrestin2 prevented P2Y2 receptor desensitization and enhanced and prolonged p38 and ERK MAPK signals, while arrestin3 depletion was ineffective. Conversely, arrestin3 knockdown prevented ETA receptor desensitization and attenuated ET1-stimulated p38 and ERK signals, while arrestin2 depletion had no effect. Using Transwell assays to assess agonist-stimulated ASMC migration, we found that UTP-stimulated migration was markedly attenuated following arrestin2 depletion, while ET1-stimulated migration was attenuated following knockdown of either arrestin. These data highlight a differential arrestin-dependent regulation of ETA and P2Y2 receptor-stimulated MAPK signaling. GRK2 and arrestin expression are essential for agonist-stimulated ASMC migration, which, as a key process in vascular remodeling, highlights the potential roles of GRK2 and arrestin proteins in the progression of vascular disease.
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Cao, Yubo, Sahil Kumar, Yoon Namkung, Laurence Gagnon, Aaron Cho i Stéphane A. Laporte. "Angiotensin II type 1 receptor variants alter endosomal receptor–β-arrestin complex stability and MAPK activation". Journal of Biological Chemistry 295, nr 38 (23.07.2020): 13169–80. http://dx.doi.org/10.1074/jbc.ra120.014330.
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The angiotensin II (AngII) type 1 receptor (AT1R), a member of the G protein–coupled receptor (GPCR) family, signals through G proteins and β-arrestins, which act as adaptors to regulate AT1R internalization and mitogen-activated protein kinase (MAPK) ERK1/2 activation. β-arrestin–dependent ERK1/2 regulation is the subject of important studies because its spatiotemporal control remains poorly understood for many GPCRs, including AT1R. To study the link between β-arrestin–dependent trafficking and ERK1/2 signaling, we investigated three naturally occurring AT1R variants that show distinct receptor–β-arrestin interactions: A163T, T282M, and C289W. Using bioluminescence resonance energy transfer (BRET)–based and conformational fluorescein arsenical hairpin–BRET sensors coupled with high-resolution fluorescence microscopy, we show that all AT1R variants form complexes with β-arrestin2 at the plasma membrane and efficiently internalize into endosomes upon AngII stimulation. However, mutant receptors imposed distinct conformations in β-arrestin2 and differentially impacted endosomal trafficking and MAPK signaling. Notably, T282M accumulated in endosomes, but its ability to form stable complexes following internalization was reduced, markedly impairing its ability to co-traffic with β-arrestin2. We also found that despite β-arrestin2 overexpression, T282M's and C289W's residency with β-arrestin2 in endosomes was greatly reduced, leading to decreased β-arrestin–dependent ERK1/2 activation, faster recycling of receptors to the plasma membrane, and impaired AngII-mediated proliferation. Our findings reveal that naturally occurring AT1R variants alter the patterns of receptor/β-arrestin2 trafficking and suggest conformationally dependent β-arrestin–mediated MAPK activation as well as endosomal receptor–β-arrestin complex stabilization in the mitogenic response of AT1R.
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Zarca, Aurélien, Claudia Perez, Jelle van den Bor, Jan Paul Bebelman, Joyce Heuninck, Rianna J. F. de Jonker, Thierry Durroux, Henry F. Vischer, Marco Siderius i Martine J. Smit. "Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization". Cells 10, nr 3 (11.03.2021): 618. http://dx.doi.org/10.3390/cells10030618.
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Background: The atypical chemokine receptor 3 (ACKR3) belongs to the superfamily of G protein-coupled receptors (GPCRs). Unlike classical GPCRs, this receptor does not activate G proteins in most cell types but recruits β-arrestins upon activation. ACKR3 plays an important role in cancer and vascular diseases. As recruitment of β-arrestins is triggered by phosphorylation of the C-terminal tail of GPCRs, we studied the role of different potential phosphorylation sites within the ACKR3 C-tail to further delineate the molecular mechanism of internalization and trafficking of this GPCR. Methods: We used various bioluminescence and fluorescence resonance energy transfer-based sensors and techniques in Human Embryonic Kidney (HEK) 293T cells expressing WT or phosphorylation site mutants of ACKR3 to measure CXCL12-induced recruitment of β-arrestins and G-protein-coupled receptor kinases (GRKs), receptor internalization and trafficking. Results: Upon CXCL12 stimulation, ACKR3 recruits both β-arrestin 1 and 2 with equivalent kinetic profiles. We identified interactions with GRK2, 3 and 5, with GRK2 and 3 being important for β-arrestin recruitment. Upon activation, ACKR3 internalizes and recycles back to the cell membrane. We demonstrate that β-arrestin recruitment to the receptor is mainly determined by a single cluster of phosphorylated residues on the C-tail of ACKR3, and that residue T352 and in part S355 are important residues for β-arrestin1 recruitment. Phosphorylation of the C-tail appears essential for ligand-induced internalization and important for differential β-arrestin recruitment. GRK2 and 3 play a key role in receptor internalization. Moreover, ACKR3 can still internalize when β-arrestin recruitment is impaired or in the absence of β-arrestins, using alternative internalization pathways. Our data indicate that distinct residues within the C-tail of ACKR3 differentially regulate CXCL12-induced β-arrestin recruitment, ACKR3 trafficking and internalization.
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Nakaya, Michio, Satsuki Chikura, Kenji Watari, Natsumi Mizuno, Koji Mochinaga, Supachoke Mangmool, Satoru Koyanagi i in. "Induction of Cardiac Fibrosis by β-Blocker in G Protein-independent and G Protein-coupled Receptor Kinase 5/β-Arrestin2-dependent Signaling Pathways". Journal of Biological Chemistry 287, nr 42 (10.08.2012): 35669–77. http://dx.doi.org/10.1074/jbc.m112.357871.
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G-protein coupled receptors (GPCRs) have long been known as receptors that activate G protein-dependent cellular signaling pathways. In addition to the G protein-dependent pathways, recent reports have revealed that several ligands called “biased ligands” elicit G protein-independent and β-arrestin-dependent signaling through GPCRs (biased agonism). Several β-blockers are known as biased ligands. All β-blockers inhibit the binding of agonists to the β-adrenergic receptors. In addition to β-blocking action, some β-blockers are reported to induce cellular responses through G protein-independent and β-arrestin-dependent signaling pathways. However, the physiological significance induced by the β-arrestin-dependent pathway remains much to be clarified in vivo. Here, we demonstrate that metoprolol, a β1-adrenergic receptor-selective blocker, could induce cardiac fibrosis through a G protein-independent and β-arrestin2-dependent pathway. Metoprolol, a β-blocker, increased the expression of fibrotic genes responsible for cardiac fibrosis in cardiomyocytes. Furthermore, metoprolol induced the interaction between β1-adrenergic receptor and β-arrestin2, but not β-arrestin1. The interaction between β1-adrenergic receptor and β-arrestin2 by metoprolol was impaired in the G protein-coupled receptor kinase 5 (GRK5)-knockdown cells. Metoprolol-induced cardiac fibrosis led to cardiac dysfunction. However, the metoprolol-induced fibrosis and cardiac dysfunction were not evoked in β-arrestin2- or GRK5-knock-out mice. Thus, metoprolol is a biased ligand that selectively activates a G protein-independent and GRK5/β-arrestin2-dependent pathway, and induces cardiac fibrosis. This study demonstrates the physiological importance of biased agonism, and suggests that G protein-independent and β-arrestin-dependent signaling is a reason for the diversity of the effectiveness of β-blockers.
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Qu, Changxiu, Ji Young Park, Min Woo Yun, Qing-tao He, Fan Yang, Kiae Kim, Donghee Ham i in. "Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade". Proceedings of the National Academy of Sciences 118, nr 37 (10.09.2021): e2026491118. http://dx.doi.org/10.1073/pnas.2026491118.
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Arrestins were initially identified for their role in homologous desensitization and internalization of G protein–coupled receptors. Receptor-bound arrestins also initiate signaling by interacting with other signaling proteins. Arrestins scaffold MAPK signaling cascades, MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. In particular, arrestins facilitate ERK1/2 activation by scaffolding ERK1/2 (MAPK), MEK1 (MAP2K), and Raf (MAPK3). However, the structural mechanism underlying this scaffolding remains unknown. Here, we investigated the mechanism of arrestin-2 scaffolding of cRaf, MEK1, and ERK2 using hydrogen/deuterium exchange–mass spectrometry, tryptophan-induced bimane fluorescence quenching, and NMR. We found that basal and active arrestin-2 interacted with cRaf, while only active arrestin-2 interacted with MEK1 and ERK2. The ATP binding status of MEK1 or ERK2 affected arrestin-2 binding; ATP-bound MEK1 interacted with arrestin-2, whereas only empty ERK2 bound arrestin-2. Analysis of the binding interfaces suggested that the relative positions of cRaf, MEK1, and ERK2 on arrestin-2 likely facilitate sequential phosphorylation in the signal transduction cascade.
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Kumar, P., C. S. Lau, M. Mathur, P. Wang i K. A. DeFea. "Differential effects of β-arrestins on the internalization, desensitization and ERK1/2 activation downstream of protease activated receptor-2". American Journal of Physiology-Cell Physiology 293, nr 1 (lipiec 2007): C346—C357. http://dx.doi.org/10.1152/ajpcell.00010.2007.
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β-Arrestins-1 and 2 are known to play important roles in desensitization of membrane receptors and facilitation of signal transduction pathways. It has been previously shown that β-arrestins are required for signal termination, internalization, and ERK1/2 activation downstream of protease-activated-receptor-2 (PAR-2), but it is unclear whether they are functionally redundant or mediate specific events. Here, we demonstrate that in mouse embryonic fibroblasts (MEFs) from β-arrestin-1/2 knockout mice, Gαq signaling by PAR-2, as measured by mobilization of intracellular Ca2+, is prolonged. Only expression of β-arrestin-1 shortened the signal duration, whereas either β-arrestin-1 or 2 was able to restore PKC-induced receptor desensitization. β-arrestin-1 also mediated early, while β-arrestin-2 mediated delayed, receptor internalization and membrane-associated ERK1/2 activation. While β-arrestin-1 colocalized with a lysosomal marker (LAMP-1), β-arrestin-2 did not, suggesting a specific role for β-arrestin-1 in lysosomal receptor degradation. Together, these data suggest distinct temporal and functional roles for β-arrestins in PAR-2 signaling, desensitization, and internalization.
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Spillmann, Martin, Larissa Thurner, Nina Romantini, Mirjam Zimmermann, Benoit Meger, Martin Behe, Maria Waldhoer, Gebhard F. X. Schertler i Philipp Berger. "New Insights into Arrestin Recruitment to GPCRs". International Journal of Molecular Sciences 21, nr 14 (13.07.2020): 4949. http://dx.doi.org/10.3390/ijms21144949.
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G protein-coupled receptors (GPCRs) are cellular master regulators that translate extracellular stimuli such as light, small molecules or peptides into a cellular response. Upon ligand binding, they bind intracellular proteins such as G proteins or arrestins, modulating intracellular signaling cascades. Here, we use a protein-fragment complementation approach based on nanoluciferase (split luciferase assay) to assess interaction of all four known human arrestins with four different GPCRs (two class A and two class B receptors) in live cells. Besides directly tagging the 11S split-luciferase subunit to the receptor, we also could demonstrate that membrane localization of the 11S subunit with a CAAX-tag allowed us to probe arrestin recruitment by endogenously expressed GPCRs. Varying the expression levels of our reporter constructs changed the dynamic behavior of our assay, which we addressed with an advanced baculovirus-based multigene expression system. Our detection assay allowed us to probe the relevance of each of the two arrestin binding sites in the different GPCRs for arrestin binding. We observed remarkable differences between the roles of each arresting binding site in the tested GPCRs and propose that the distinct advantages of our system for probing receptor interaction with effector proteins will help elucidate the molecular basis of GPCR signaling efficacy and specificity in different cell types.
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Qian, Hongwei, Luisa Pipolo i Walter G. Thomas. "Association of β-Arrestin 1 with the Type 1A Angiotensin II Receptor Involves Phosphorylation of the Receptor Carboxyl Terminus and Correlates with Receptor Internalization". Molecular Endocrinology 15, nr 10 (1.10.2001): 1706–19. http://dx.doi.org/10.1210/mend.15.10.0714.
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Abstract Arrestins bind to phosphorylated G protein-coupled receptors and participate in receptor desensitization and endocytosis. Although arrestins traffic with activated type 1 (AT1A) angiotensin II (AngII) receptors, the contribution of arrestins to AT1A receptor internalization is controversial, and the physical association of arrestins with the AT1A receptor has not been established. In this study, by coimmunoprecipitating AT1A receptors and β-arrestin 1, we provide direct evidence for an association between arrestins and the AT1A receptor that was agonist- and time-dependent and contingent upon the level ofβ -arrestin 1 expression. Serial truncation of the receptor carboxyl terminus resulted in a graded loss of β-arrestin 1 association, which correlated with decreases in receptor phosphorylation. Truncation of the AT1A receptor to lysine325 prevented AngII-induced phosphorylation and β-arrestin 1 association as well as markedly inhibiting receptor internalization, indicating a close correlation between these receptor parameters. AngII-induced association was also dramatically reduced in a phosphorylation- and internalization-impaired receptor mutant in which four serine and threonine residues in the central portion of the AT1A receptor carboxyl terminus (Thr332, Ser335, Thr336, Ser338) were substituted with alanine. In contrast, substitutions in another serine/threonine-rich region (Ser346, Ser347, Ser348) and at three PKC phosphorylation sites (Ser331, Ser338, Ser348) had no effect on AngII-inducedβ -arrestin 1 association or receptor internalization. While AT1A receptor internalization could be inhibited by a dominant-negative β-arrestin 1 mutant (βarr1319–418), treatment with hyperosmotic sucrose to inhibit internalization did not abrogate the differences in arrestin association observed between the wild-type and mutant receptors, indicating that arrestin binding precedes, and is not dependent upon, receptor internalization. Interestingly, a substituted analog of AngII,[ Sar1Ile4Ile8]-AngII, which promotes robust phosphorylation of the receptor but does not activate receptor signaling, stimulated strong β-arrestin 1 association with the full-length AT1A receptor. These results identify the central portion of the AT1A receptor carboxyl terminus as the important determinant for β-arrestin 1 binding and internalization and indicate that AT1A receptor phosphorylation is crucial for β-arrestin docking.
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Wess, Jürgen. "The Two β-Arrestins Regulate Distinct Metabolic Processes: Studies with Novel Mutant Mouse Models". International Journal of Molecular Sciences 23, nr 1 (2.01.2022): 495. http://dx.doi.org/10.3390/ijms23010495.
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The two β-arrestins (β-arrestin-1 and -2; alternative names: arrestin-2 and -3, respectively) are well known for their ability to inhibit signaling via G protein-coupled receptors. However, β-arrestins can also act as signaling molecules in their own right. Although the two proteins share a high degree of sequence and structural homology, early studies with cultured cells indicated that β-arrestin-1 and -2 are not functionally redundant. Recently, the in vivo metabolic roles of the two β-arrestins have been studied using mutant mice selectively lacking either β-arrestin-1 or -2 in cell types that are of particular relevance for regulating glucose and energy homeostasis. These studies demonstrated that the β-arrestin-1 and -2 mutant mice displayed distinct metabolic phenotypes in vivo, providing further evidence for the functional heterogeneity of these two highly versatile signaling proteins.
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Li, Dongjun, i Donna S. Woulfe. "Arrestin-2 Regulates Akt Activation by G Protein-Coupled Receptors in Platelets." Blood 108, nr 11 (16.11.2006): 1525. http://dx.doi.org/10.1182/blood.v108.11.1525.1525.
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Abstract Arrestins have been shown to play important roles in G Protein-Coupled Receptor (GPCR) function in many cells, but their roles in platelets remain uncharacterized. While the classical role of arrestins is considered to be the internalization and desensitization of GPCRs, more recent studies suggest that arrestins can serve as scaffolds to recruit phosphatidyl inositol-3 kinases (PI3K)s to Gq-coupled receptors and promote PI3K-dependent signaling. Thrombin stimulates the PI3K-dependent activation of Akt in platelets in a Gq-dependent manner. Therefore, we sought to determine whether arrestins are involved in the PI3K-dependent activation of Akt in platelets. Comparative immunoblots show that of the two non-visual mammalian arrestins, only one, arrestin-2 (β-arrestin-1), is expressed in human and mouse platelets. Immunoprecipitation of arrestin-2 or p85-PI3K from platelet lysates demonstrated that arrestin-2 associates with the p85 subunit of PI3Ka/b in thrombin or ADP-stimulated platelets, but not resting cells. The association can be inhibited by inhibitors of the P2Y12 receptor for ADP, but not by P2Y1 inhibitors. p85-arrestin association is also blocked by inhibitors of src family kinases, as is Akt phosphorylation. To determine whether src family members were part of the p85-arrestin complexes, immunoblots were re-probed with antibodies to src, lyn and fyn. The results show that Lyn is incorporated into thrombin-stimulated arrestin complexes in a P2Y12-dependent manner. To determine whether arrestin-2 is important for Akt phosphorylation in platelets, megakaryocytes differentiated in culture from mouse embryonic stem cells were used as models of platelet signaling, since these cells are amenable to genetic manipulation. Arrestin-2 was inhibited in the cultured megakaryocytes using a siRNA approach, then cells were stimulated with thrombin and Akt phosphorylation was assessed by immunoblotting. Arrestin-2 expression in the cultured megakaryocytes treated with arrestin-2 specific siRNA was suppressed by an average of 53% compared to cells treated with scrambled siRNA, while thrombin-stimulated Akt phosphorylation was suppressed by 98% compared to scrambled siRNA-treated control cells (n=3 experiments, difference is significant, p=.01, unpaired student’s t-test). In conclusion, the results show that arrestin-2, lyn and PI3Kform a tri-molecular complex following stimulation of platelets with ADP or thrombin. Formation of arrestin complexes at activated receptor sites is important for the localized recruitment and src-dependent activation of p85-PI3K, thus promoting activation of Akt by G protein-coupled receptors.
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Wang, Yandao, Jieli Huang, Xi Liu, Yangyang Niu, Liqin Zhao, Ying Yu, Li Zhou, Limin Lu i Chen Yu. "β-Arrestin-biased AT1R stimulation promotes extracellular matrix synthesis in renal fibrosis". American Journal of Physiology-Renal Physiology 313, nr 1 (1.07.2017): F1—F8. http://dx.doi.org/10.1152/ajprenal.00588.2016.
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The renin-angiotensin system plays a critical role in the progression of renal fibrosis. Angiotensin II type 1 receptor (AT1R) belongs to the B family of the G protein-coupled receptor (GPCR) family. β-Arrestins are known as negative regulators of GPCRs. Recently, β-arrestins have been found to regulate multiple intracellular signaling pathways independent of G proteins. In this study we investigated the role of β-arrestins in regulating extracellular matrix (ECM) synthesis in renal fibrosis. The rat kidney fibroblast cell line (NRK-49F) was treated with the β-arrestin biased agonist [1-sar, 4, 8-ile]angiotensin II (SII), which does not initiate AT1R-G protein signaling. The cells were transfected with recombinant adenoviruses expressing β-arrestin-2 gene or small-interfering RNA (siRNA) targeting β-arrestin-2. The unilateral ureteral obstruction (UUO) model was used in vivo. mRNA and protein levels of β-arrestin-2, not β-arrestin-1, were significantly upregulated in the UUO kidney tissues. SII induced the tight binding of β-arrestin-2 with AT1R. SII increased the synthesis of collagen I and fibronectin in NRK-49F, which were abolished when pretreated with candesartan (AT1R blocker). Transfection of siRNA targeting β-arrestin-2 decreased the effects of SII on ECM synthesis. Overexpression of β-arrestin-2 enhanced SII-stimulated ECM synthesis. SII induced ERK1/2 phosphorylation in NRK-49F. Transfection of siRNA targeting β-arrestin-2 inhibited ERK phosphorylation. Overexpression of β-arrestin-2 increased ERK1/2 phosphorylation. Our study first showed that AT1R-β-arrestin-2 pathway signaling plays an important role in renal fibrosis, although it was previously believed that the AT1R-G protein pathway plays a major role. Targeting β-arrestin-2 may be a potential therapeutic agent for renal fibrosis.
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Golan, Moran, Gabriel Schreiber i Sofia Avissar. "Antidepressant-induced differential ubiquitination of β-arrestins 1 and 2 in mononuclear leucocytes of patients with depression". International Journal of Neuropsychopharmacology 16, nr 8 (1.09.2013): 1745–54. http://dx.doi.org/10.1017/s1461145713000291.
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Abstract β-Arrestins 1 and 2, cytosolic proteins known to mediate receptor desensitization, endocytosis and G protein-independent signalling, are post-translationally modified by ubiquitination regulating their ability to serve as adaptors and scaffolds. β-Arrestins were suggested to play a role in the pathophysiology of depression and in antidepressant mechanism of action. To determine whether a depressive episode or antidepressant treatment induce significant selective differences in β-arrestin 1 and 2 levels or their ubiquitination patterns in leucocytes of patients with depression, 46 outpatients diagnosed with a depressive episode were examined before and after 4-wk antidepressant treatment compared with age- and gender-matched control subjects. β-Arrestin levels were measured by immunoblotting using anti-arrestin antibodies. Ubiquitination of β-arrestins was measured using anti-ubiquitin antibodies followed by an immunoprecipitation step and immunoblotting using anti-arrestin antibodies. Antidepressants induced selective alterations in leucocyte β-arrestin 1 and 2 levels and ubiquitination. The levels of β-arrestin 1 and 2 and their ubiquitinated forms in leucocytes of yet untreated patients with depression were significantly decreased in a symptom severity correlated manner compared to control subjects. Antidepressants normalized β-arrestin 1 and 2 levels and uncovered novel differences between the two isoforms: (a) while antidepressants normalized ubiquitination of β-arrestin 1, ubiquination of β-arrestin 2 was unaffected; (b) while under antidepressants ubiquitination extent of β-arrestin 1 positively correlated with its level, an inverse picture of negative correlation was found between ubiquitination extent of β-arrestin 2 and its level. We conclude that antidepressants may serve as a tool to detect functional differences between the two β-arrestin isoforms and that through these differential effects antidepressants can induce specific alterations in alternative cellular signalling.
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Vishnivetskiy, Sergey A., Luis E. Gimenez, Derek J. Francis, Susan M. Hanson, Wayne L. Hubbell, Candice S. Klug i Vsevolod V. Gurevich. "Few Residues within an Extensive Binding Interface Drive Receptor Interaction and Determine the Specificity of Arrestin Proteins". Journal of Biological Chemistry 286, nr 27 (6.04.2011): 24288–99. http://dx.doi.org/10.1074/jbc.m110.213835.
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Arrestins bind active phosphorylated forms of G protein-coupled receptors, terminating G protein activation, orchestrating receptor trafficking, and redirecting signaling to alternative pathways. Visual arrestin-1 preferentially binds rhodopsin, whereas the two non-visual arrestins interact with hundreds of G protein-coupled receptor subtypes. Here we show that an extensive surface on the concave side of both arrestin-2 domains is involved in receptor binding. We also identified a small number of residues on the receptor binding surface of the N- and C-domains that largely determine the receptor specificity of arrestins. We show that alanine substitution of these residues blocks the binding of arrestin-1 to rhodopsin in vitro and of arrestin-2 and -3 to β2-adrenergic, M2 muscarinic cholinergic, and D2 dopamine receptors in intact cells, suggesting that these elements critically contribute to the energy of the interaction. Thus, in contrast to arrestin-1, where direct phosphate binding is crucial, the interaction of non-visual arrestins with their cognate receptors depends to a lesser extent on phosphate binding and more on the binding to non-phosphorylated receptor elements.
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BATTELLE, B.-A., A. W. ANDREWS, K. E. KEMPLER, S. C. EDWARDS i W. C. SMITH. "Visual arrestin in Limulus is phosphorylated at multiple sites in the light and in the dark". Visual Neuroscience 17, nr 5 (wrzesień 2000): 813–22. http://dx.doi.org/10.1017/s0952523800175145.
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Arrestins participate in the termination of phototransduction in both vertebrates and invertebrates. However, the visual arrestins of invertebrates and vertebrates differ significantly from one another in that the invertebrate visual arrestins become phosphorylated rapidly in response to light while those in the photoreceptors of vertebrates do not. In an effort to understand the functional relevance of arrestin phosphorylation, we examined this process in the photoreceptors of the horseshoe crab Limulus polyphemus. We report that Limulus visual arrestin can be phosphorylated at three sites near its C-terminus and show that arrestin molecules phosphorylated on one, two, and three sites are normally present in both light- and dark-adapted photoreceptors. Light adaptation increases the amount of arrestin phosphorylated at three sites.
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Karnam, Preethi C., Sergey A. Vishnivetskiy i Vsevolod V. Gurevich. "Structural Basis of Arrestin Selectivity for Active Phosphorylated G Protein-Coupled Receptors". International Journal of Molecular Sciences 22, nr 22 (19.11.2021): 12481. http://dx.doi.org/10.3390/ijms222212481.
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Arrestins are a small family of proteins that bind G protein-coupled receptors (GPCRs). Arrestin binds to active phosphorylated GPCRs with higher affinity than to all other functional forms of the receptor, including inactive phosphorylated and active unphosphorylated. The selectivity of arrestins suggests that they must have two sensors, which detect receptor-attached phosphates and the active receptor conformation independently. Simultaneous engagement of both sensors enables arrestin transition into a high-affinity receptor-binding state. This transition involves a global conformational rearrangement that brings additional elements of the arrestin molecule, including the middle loop, in contact with a GPCR, thereby stabilizing the complex. Here, we review structural and mutagenesis data that identify these two sensors and additional receptor-binding elements within the arrestin molecule. While most data were obtained with the arrestin-1-rhodopsin pair, the evidence suggests that all arrestins use similar mechanisms to achieve preferential binding to active phosphorylated GPCRs.
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Gatto, Federico, Richard A. Feelders, Rob van der Pas, Peter van Koetsveld, Eleonora Bruzzone, Marica Arvigo, Fadime Dogan, Steven Lamberts, Diego Ferone i Leo Hofland. "β-arrestin expression in corticotroph tumor cells is modulated by glucocorticoids". Journal of Endocrinology 245, nr 1 (kwiecień 2020): 101–13. http://dx.doi.org/10.1530/joe-19-0311.
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Pituitary-directed medical treatment for Cushing’s disease (CD) is currently represented by membrane receptor targeting drugs (somatostatin analogs and dopamine agonists). Somatostatin and dopamine receptors are regulated by β-arrestins, which have been shown to be differentially regulated by glucocorticoids in non-neuroendocrine cells. In this study we investigated the effects of glucocorticoids on β-arrestin expression in corticotroph tumor cells. First, AtT20 cells, a mouse model of CD, were exposed to dexamethasone (Dex) at different time points and β-arrestin expression was evaluated at mRNA and protein levels. Futhermore, β-arrestin mRNA expression was evaluated in 17 human corticotroph adenoma samples and correlated to patients’ pre-operative cortisol levels. We observed that Dex treatment induced a time-dependent increase in β-arrestin 1 mRNA expression and a decrease in β-arrestin 2. The same modulation pattern was observed at protein level. Dex-mediated modulation of β-arrestins was abolished by co-treatment with mifepristone, and Dex withdrawal restored β-arrestin expression to basal levels after 72 h. The evaluation of β-arrestin mRNA in corticotroph adenomas from CD patients with variable disease activity showed a significant positive correlation between β-arrestin 1 mRNA and urinary cortisol levels. The effect of glucocorticoids on β-arrestin levels was confirmed by the analysis of two samples from a single patient, which underwent adenomectomy twice, with different pre-operative cortisol levels. In conclusion, glucocorticoids induce an inverse modulation of the two β-arrestin isofoms in corticotroph tumor cells. Since β-arrestins regulate membrane receptor functions, this finding may help to better understand the variable response to pituitary-targeting drugs in patients with Cushing’s disease.
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Vishnivetskiy, Sergey A., Elizabeth K. Huh, Preethi C. Karnam, Samantha Oviedo, Eugenia V. Gurevich i Vsevolod V. Gurevich. "The Role of Arrestin-1 Middle Loop in Rhodopsin Binding". International Journal of Molecular Sciences 23, nr 22 (11.11.2022): 13887. http://dx.doi.org/10.3390/ijms232213887.
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Arrestins preferentially bind active phosphorylated G protein-coupled receptors (GPCRs). The middle loop, highly conserved in all arrestin subtypes, is localized in the central crest on the GPCR-binding side. Upon receptor binding, it directly interacts with bound GPCR and demonstrates the largest movement of any arrestin element in the structures of the complexes. Comprehensive mutagenesis of the middle loop of rhodopsin-specific arrestin-1 suggests that it primarily serves as a suppressor of binding to non-preferred forms of the receptor. Several mutations in the middle loop increase the binding to unphosphorylated light-activated rhodopsin severalfold, which makes them candidates for improving enhanced phosphorylation-independent arrestins. The data also suggest that enhanced forms of arrestin do not bind GPCRs exactly like the wild-type protein. Thus, the structures of the arrestin-receptor complexes, in all of which different enhanced arrestin mutants and reengineered receptors were used, must be interpreted with caution.
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Willets, Jonathon M., Craig A. Nash, Richard D. Rainbow, Carl P. Nelson i R. A. John Challiss. "Defining the roles of arrestin2 and arrestin3 in vasoconstrictor receptor desensitization in hypertension". American Journal of Physiology-Cell Physiology 309, nr 3 (1.08.2015): C179—C189. http://dx.doi.org/10.1152/ajpcell.00079.2015.
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Prolonged vasoconstrictor-stimulated phospholipase C activity can induce arterial constriction, hypertension, and smooth muscle hypertrophy/hyperplasia. Arrestin proteins are recruited by agonist-occupied G protein-coupled receptors to terminate signaling and counteract changes in vascular tone. Here we determine whether the development of hypertension affects arrestin expression in resistance arteries and how such changes alter arterial contractile signaling and function. Arrestin2/3 expression was increased in mesenteric arteries of 12-wk-old spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) controls, while no differences in arrestin expression were observed between 6-wk-old SHR and WKY animals. In mesenteric artery myography experiments, high extracellular K+-stimulated contractions were increased in both 6- and 12-wk-old SHR animals. Concentration-response experiments for uridine 5′-triphosphate (UTP) acting through P2Y receptors displayed a leftward shift in 12-wk, but not 6-wk-old animals. Desensitization of UTP-stimulated vessel contractions was increased in 12-wk-old (but not 6-wk-old) SHR animals. Dual IP3/Ca2+ imaging in mesenteric arterial cells showed that desensitization of UTP and endothelin-1 (ET1) responses was enhanced in 12-wk-old (but not 6-wk-old) SHR compared with WKY rats. siRNA-mediated depletion of arrestin2 for UTP and arrestin3 for ET1, reversed the desensitization of PLC signaling. In conclusion, arrestin2 and 3 expression is elevated in resistance arteries during the emergence of the early hypertensive phenotype, which underlies an enhanced ability to desensitize vasoconstrictor signaling and vessel contraction. Such regulatory changes may act to compensate for increased vasoconstrictor-induced vessel contraction.
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Kleist, Andrew B., Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie I. Anderson i in. "Conformational selection guides β-arrestin recruitment at a biased G protein–coupled receptor". Science 377, nr 6602 (8.07.2022): 222–28. http://dx.doi.org/10.1126/science.abj4922.
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G protein–coupled receptors (GPCRs) recruit β-arrestins to coordinate diverse cellular processes, but the structural dynamics driving this process are poorly understood. Atypical chemokine receptors (ACKRs) are intrinsically biased GPCRs that engage β-arrestins but not G proteins, making them a model system for investigating the structural basis of β-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13 CH 3 -ε–methionine–labeled ACKR3, revealing that β-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular β-arrestin–coupling region. NMR studies of ACKR3 mutants defective in β-arrestin recruitment identified an allosteric hub in the receptor core that coordinates transitions among heterogeneously populated and selected conformational states. Our data suggest that conformational selection guides β-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.
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Zbieralski, Kacper, i Donata Wawrzycka. "α-Arrestins and Their Functions: From Yeast to Human Health". International Journal of Molecular Sciences 23, nr 9 (30.04.2022): 4988. http://dx.doi.org/10.3390/ijms23094988.
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α-Arrestins, also called arrestin-related trafficking adaptors (ARTs), constitute a large family of proteins conserved from yeast to humans. Despite their evolutionary precedence over their extensively studied relatives of the β-arrestin family, α-arrestins have been discovered relatively recently, and thus their properties are mostly unexplored. The predominant function of α-arrestins is the selective identification of membrane proteins for ubiquitination and degradation, which is an important element in maintaining membrane protein homeostasis as well as global cellular metabolisms. Among members of the arrestin clan, only α-arrestins possess PY motifs that allow canonical binding to WW domains of Rsp5/NEDD4 ubiquitin ligases and the subsequent ubiquitination of membrane proteins leading to their vacuolar/lysosomal degradation. The molecular mechanisms of the selective substrate’s targeting, function, and regulation of α-arrestins in response to different stimuli remain incompletely understood. Several functions of α-arrestins in animal models have been recently characterized, including redox homeostasis regulation, innate immune response regulation, and tumor suppression. However, the molecular mechanisms of α-arrestin regulation and substrate interactions are mainly based on observations from the yeast Saccharomyces cerevisiae model. Nonetheless, α-arrestins have been implicated in health disorders such as diabetes, cardiovascular diseases, neurodegenerative disorders, and tumor progression, placing them in the group of potential therapeutic targets.
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Kim, Kiae, Yeonjin Han, Longhan Duan i Ka Young Chung. "Scaffolding of Mitogen-Activated Protein Kinase Signaling by β-Arrestins". International Journal of Molecular Sciences 23, nr 2 (17.01.2022): 1000. http://dx.doi.org/10.3390/ijms23021000.
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β-arrestins were initially identified to desensitize and internalize G-protein-coupled receptors (GPCRs). Receptor-bound β-arrestins also initiate a second wave of signaling by scaffolding mitogen-activated protein kinase (MAPK) signaling components, MAPK kinase kinase, MAPK kinase, and MAPK. In particular, β-arrestins facilitate ERK1/2 or JNK3 activation by scaffolding signal cascade components such as ERK1/2-MEK1-cRaf or JNK3-MKK4/7-ASK1. Understanding the precise molecular and structural mechanisms of β-arrestin-mediated MAPK scaffolding assembly would deepen our understanding of GPCR-mediated MAPK activation and provide clues for the selective regulation of the MAPK signaling cascade for therapeutic purposes. Over the last decade, numerous research groups have attempted to understand the molecular and structural mechanisms of β-arrestin-mediated MAPK scaffolding assembly. Although not providing the complete mechanism, these efforts suggest potential binding interfaces between β-arrestins and MAPK signaling components and the mechanism for MAPK signal amplification by β-arrestin-mediated scaffolding. This review summarizes recent developments of cellular and molecular works on the scaffolding mechanism of β-arrestin for MAPK signaling cascade.
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Liu, Xing, Li Ma, Hao Hong Li, Bing Huang, You Xing Li, Ye Zheng Tao i Lan Ma. "β-Arrestin–biased signaling mediates memory reconsolidation". Proceedings of the National Academy of Sciences 112, nr 14 (23.03.2015): 4483–88. http://dx.doi.org/10.1073/pnas.1421758112.
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A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates β-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of β1-adrenergic β-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. β-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, and cocaine-conditioned place preference paradigms. Postreactivation blockade of both brain β-adrenergic Gs protein- and β-arrestin–dependent pathways disrupts memory reconsolidation. Unexpectedly, selective blockade of the Gs/cAMP/PKA signaling but not the β-arrestin/ERK signaling by the biased β-adrenergic ligands does not inhibit reconsolidation. Moreover, the expression of β-arrestin2 in the entorhinal cortex of β-arrestin 2–deficient mice rescues β1-adrenergic ERK signaling and reconsolidation in a G protein pathway-independent manner. We demonstrate that β-arrestin–biased signaling regulates memory reconsolidation and reveal the potential for β-arrestin–biased ligands in the treatment of memory-related disorders.
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Seyedabadi, Mohammad, Mehdi Gharghabi, Eugenia V. Gurevich i Vsevolod V. Gurevich. "Receptor-Arrestin Interactions: The GPCR Perspective". Biomolecules 11, nr 2 (4.02.2021): 218. http://dx.doi.org/10.3390/biom11020218.
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Arrestins are a small family of four proteins in most vertebrates that bind hundreds of different G protein-coupled receptors (GPCRs). Arrestin binding to a GPCR has at least three functions: precluding further receptor coupling to G proteins, facilitating receptor internalization, and initiating distinct arrestin-mediated signaling. The molecular mechanism of arrestin–GPCR interactions has been extensively studied and discussed from the “arrestin perspective”, focusing on the roles of arrestin elements in receptor binding. Here, we discuss this phenomenon from the “receptor perspective”, focusing on the receptor elements involved in arrestin binding and emphasizing existing gaps in our knowledge that need to be filled. It is vitally important to understand the role of receptor elements in arrestin activation and how the interaction of each of these elements with arrestin contributes to the latter’s transition to the high-affinity binding state. A more precise knowledge of the molecular mechanisms of arrestin activation is needed to enable the construction of arrestin mutants with desired functional characteristics.
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Pydi, Sai P., Luiz F. Barella, Lu Zhu, Jaroslawna Meister, Mario Rossi i Jürgen Wess. "β-Arrestins as Important Regulators of Glucose and Energy Homeostasis". Annual Review of Physiology 84, nr 1 (10.02.2022): 17–40. http://dx.doi.org/10.1146/annurev-physiol-060721-092948.
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β-Arrestin-1 and -2 (also known as arrestin-2 and -3, respectively) are ubiquitously expressed cytoplasmic proteins that dampen signaling through G protein–coupled receptors. However, β-arrestins can also act as signaling molecules in their own right. To investigate the potential metabolic roles of the two β-arrestins in modulating glucose and energy homeostasis, recent studies analyzed mutant mice that lacked or overexpressed β-arrestin-1 and/or -2 in distinct, metabolically important cell types. Metabolic analysis of these mutant mice clearly demonstrated that both β-arrestins play key roles in regulating the function of most of these cell types, resulting in striking changes in whole-body glucose and/or energy homeostasis. These studies also revealed that β-arrestin-1 and -2, though structurally closely related, clearly differ in their metabolic roles under physiological and pathophysiological conditions. These new findings should guide the development of novel drugs for the treatment of various metabolic disorders, including type 2 diabetes and obesity.
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Wang, Ping, Puneet Kumar, Chang Wang i Kathryn A. DeFea. "Differential regulation of class IA phosphoinositide 3-kinase catalytic subunits p110α and β by protease-activated receptor 2 and β-arrestins". Biochemical Journal 408, nr 2 (14.11.2007): 221–30. http://dx.doi.org/10.1042/bj20070483.
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PAR-2 (protease-activated receptor 2) is a GPCR (G-protein-coupled receptor) that can elicit both G-protein-dependent and -independent signals. We have shown previously that PAR-2 simultaneously promotes Gαq/Ca2+-dependent activation and β-arrestin-1-dependent inhibition of class IA PI3K (phosphoinositide 3-kinase), and we sought to characterize further the role of β-arrestins in the regulation of PI3K activity. Whereas the ability of β-arrestin-1 to inhibit p110α (PI3K catalytic subunit α) has been demonstrated, the role of β-arrestin-2 in PI3K regulation and possible differences in the regulation of the two catalytic subunits (p110α and p110β) associated with p85α (PI3K regulatory subunit) have not been examined. In the present study we have demonstrated that: (i) PAR-2 increases p110α- and p110β-associated lipid kinase activities, and both p110α and p110β are inhibited by over-expression of either β-arrestin-1 or -2; (ii) both β-arrestin-1 and -2 directly inhibit the p110α catalytic subunit in vitro, whereas only β-arrestin-2 directly inhibited p110β; (iii) examination of upstream pathways revealed that PAR-2-induced PI3K activity required the small GTPase Cdc (cell-division cycle)42, but not tyrosine phosphorylation of p85; and (iv) β-arrestins inhibit PAR-2-induced Cdc42 activation. Taken together, these results indicated that β-arrestins could inhibit PAR-2-stimulated PI3K activity, both directly and through interference with upstream pathways, and that the two β-arrestins differ in their ability to inhibit the p110α and p110β catalytic subunits. These results are particularly important in light of the growing interest in PAR-2 as a pharmacological target, as commonly used biochemical assays that monitor G-protein coupling would not screen for β-arrestin-dependent signalling events.
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Perry-Hauser, Nicole A., Tamer S. Kaoud, Henriette Stoy, Xuanzhi Zhan, Qiuyan Chen, Kevin N. Dalby, Tina M. Iverson, Vsevolod V. Gurevich i Eugenia V. Gurevich. "Short Arrestin-3-Derived Peptides Activate JNK3 in Cells". International Journal of Molecular Sciences 23, nr 15 (4.08.2022): 8679. http://dx.doi.org/10.3390/ijms23158679.
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Arrestins were first discovered as suppressors of G protein-mediated signaling by G protein-coupled receptors. It was later demonstrated that arrestins also initiate several signaling branches, including mitogen-activated protein kinase cascades. Arrestin-3-dependent activation of the JNK family can be recapitulated with peptide fragments, which are monofunctional elements distilled from this multi-functional arrestin protein. Here, we use maltose-binding protein fusions of arrestin-3-derived peptides to identify arrestin elements that bind kinases of the ASK1-MKK4/7-JNK3 cascade and the shortest peptide facilitating JNK signaling. We identified a 16-residue arrestin-3-derived peptide expressed as a Venus fusion that leads to activation of JNK3α2 in cells. The strength of the binding to the kinases does not correlate with peptide activity. The ASK1-MKK4/7-JNK3 cascade has been implicated in neuronal apoptosis. While inhibitors of MAP kinases exist, short peptides are the first small molecule tools that can activate MAP kinases.
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Gatto, Federico, Nienke R. Biermasz, Richard A. Feelders, Johan M. Kros, Fadime Dogan, Aart-Jan van der Lely, Sebastian J. C. M. M. Neggers i in. "Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly". European Journal of Endocrinology 174, nr 5 (maj 2016): 651–62. http://dx.doi.org/10.1530/eje-15-0391.
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AbstractObjectiveThe high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst2) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function.DesignTo investigate whether β-arrestins might be useful predictors of responsiveness to long-term SSA treatment in acromegaly, we retrospectively evaluated 35 patients with acromegaly who underwent adenomectomy in two referral centers in The Netherlands.Methodsβ-arrestin mRNA levels were evaluated in adenoma samples, together with SSTR2 (and SSTR5) mRNA and protein expression. Biochemical response to long-term SSA treatment (median 12 months) was assessed in 32 patients.Resultsβ-arrestin 1 and 2 mRNA was significantly lower in adenoma tissues from patients who achieved insulin-like growth factor 1 normalization (P= 0.024 andP= 0.047) and complete biochemical control (P= 0.047 andP= 0.039). The SSTR2 mRNA was higher in SSA responder patients compared with the resistant ones (P= 0.026). This difference was more evident when analyzing the SSTR2/β-arrestin 1 and SSTR2/β-arrestin 2 ratio (P= 0.011 andP= 0.010). β-arrestin 1 and 2 expression showed a significant trend of higher median values from full responders, partial responders to resistant patients (P= 0.045 andP= 0.021, respectively). Interestingly, SSTR2 protein expression showed a strong inverse correlation with both β-arrestin 1 and 2 mRNA (ρ= –0.69,P= 0.0011 andρ= –0.67,P= 0.0016).ConclusionsLow β-arrestin expression and high SSTR2/β-arrestin ratio correlate with the responsiveness to long-term treatment with SSAs in patients with acromegaly.
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Attramadal, H., J. L. Arriza, C. Aoki, T. M. Dawson, J. Codina, M. M. Kwatra, S. H. Snyder, M. G. Caron i R. J. Lefkowitz. "Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family." Journal of Biological Chemistry 267, nr 25 (wrzesień 1992): 17882–90. http://dx.doi.org/10.1016/s0021-9258(19)37125-x.
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Gatto, Federico, Richard Feelders, Rob van der Pas, Johan M. Kros, Fadime Dogan, Peter M. van Koetsveld, Aart-Jan van der Lelij i in. "β-Arrestin 1 and 2 and G Protein-Coupled Receptor Kinase 2 Expression in Pituitary Adenomas: Role in the Regulation of Response to Somatostatin Analogue Treatment in Patients With Acromegaly". Endocrinology 154, nr 12 (1.12.2013): 4715–25. http://dx.doi.org/10.1210/en.2013-1672.
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Recent in vitro studies highlighted G protein-coupled receptor kinase (GRK)2 and β-arrestins as important players in driving somatostatin receptor (SSTR) desensitization and trafficking. Our aim was to characterize GRK2 and β-arrestins expression in different pituitary adenomas and to investigate their potential role in the response to somatostatin analog (SSA) treatment in GH-secreting adenomas (GHomas). We evaluated mRNA expression of multiple SSTRs, GRK2, β-arrestin 1, and β-arrestin 2 in 41 pituitary adenomas (31 GHomas, 6 nonfunctioning [NFPAs], and 4 prolactinomas [PRLomas]). Within the GHomas group, mRNA data were correlated with the in vivo response to an acute octreotide test and with the GH-lowering effect of SSA in cultured primary cells. β-Arrestin 1 expression was low in all 3 adenoma histotypes. However, its expression was significantly lower in GHomas and PRLomas, compared with NFPAs (P < .01). GRK2 expression was higher in PRLomas and NFPAs compared with GHomas (P < .05). In the GHoma group, GRK2 expression was inversely correlated to β-arrestin 1 (P < .05) and positively correlated to β-arrestin 2 (P < .0001). SSA treatment did not affect GRK2 and β-arrestin expression in GHomas or in cultured rat pituitary tumor GH3 cells. Noteworthy, β-arrestin 1 was significantly lower (P < .05) in tumors responsive to octreotide treatment in vitro, whereas GRK2 and SSTR subtype 2 were significantly higher (P < .05). Likewise, β-arrestin 1 levels were inversely correlated with the in vivo response to acute octreotide test (P = .001), whereas GRK2 and SSTR subtype 2 expression were positively correlated (P < .05). In conclusion, for the first time, we characterized GRK2, β-arrestin 1, and β-arrestin 2 expression in a representative number of pituitary adenomas. β-Arrestin 1 and GRK2 seem to have a role in modulating GH secretion during SSA treatment.
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Marion, Sébastien, Elodie Kara, Pascale Crepieux, Vincent Piketty, Nadine Martinat, Florian Guillou i Eric Reiter. "G protein-coupled receptor kinase 2 and β-arrestins are recruited to FSH receptor in stimulated rat primary Sertoli cells". Journal of Endocrinology 190, nr 2 (sierpień 2006): 341–50. http://dx.doi.org/10.1677/joe.1.06857.
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FSH-receptor (FSH-R) signaling is regulated by agonist-induced desensitization and internalization. It has been shown, in a variety of overexpression systems, that G protein-coupled receptor kinases (GRKs) phosphorylate the activated FSH-R, promote β-arrestin recruitment and ultimately lead to internalization. The accuracy of this mechanism has not yet been demonstrated in cells expressing these different molecules at physiological levels. Using sucrose gradient fractionation, we show that FSH induces the recruitment of the endogenous GRK 2 and β-arrestin 1/2 from the cytoplasm to the plasma membrane of rat primary Sertoli cells. As assessed by ligand binding, the FSH-R was found expressed in the fractions where GRK 2 and β-arrestins were recruited upon FSH treatment. In addition, the endogenous β-arrestin 1 was found dephosphorylated in an agonist-dependent manner. Finally, a significant FSH-binding activity was co-immunoprecipitated with the endogenous β-arrestins from agonist-stimulated but not from untreated Sertoli cell extracts. This FSH-R interaction with β-arrestins was sustained for up to 30 min. In conclusion, our data strongly suggest that the GRK/β-arrestin machinery plays a physiologically relevant role in the regulation of the FSH signaling.
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Becuwe, Michel, Antonio Herrador, Rosine Haguenauer-Tsapis, Olivier Vincent i Sébastien Léon. "Ubiquitin-Mediated Regulation of Endocytosis by Proteins of the Arrestin Family". Biochemistry Research International 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/242764.
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In metazoans, proteins of the arrestin family are key players of G-protein-coupled receptors (GPCRS) signaling and trafficking. Following stimulation, activated receptors are phosphorylated, thus allowing the binding of arrestins and hence an “arrest” of receptor signaling. Arrestins act by uncoupling receptors from G proteins and contribute to the recruitment of endocytic proteins, such as clathrin, to direct receptor trafficking into the endocytic pathway. Arrestins also serve as adaptor proteins by promoting the recruitment of ubiquitin ligases and participate in the agonist-induced ubiquitylation of receptors, known to have impact on their subcellular localization and stability. Recently, the arrestin family has expanded following the discovery of arrestin-related proteins in other eukaryotes such as yeasts or fungi. Surprisingly, most of these proteins are also involved in the ubiquitylation and endocytosis of plasma membrane proteins, thus suggesting that the role of arrestins as ubiquitin ligase adaptors is at the core of these proteins' functions. Importantly, arrestins are themselves ubiquitylated, and this modification is crucial for their function. In this paper, we discuss recent data on the intricate connections between arrestins and the ubiquitin pathway in the control of endocytosis.
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Staus, Dean P., Laura M. Wingler, Minjung Choi, Biswaranjan Pani, Aashish Manglik, Andrew C. Kruse i Robert J. Lefkowitz. "Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in β-arrestin coupling". Proceedings of the National Academy of Sciences 115, nr 15 (26.03.2018): 3834–39. http://dx.doi.org/10.1073/pnas.1722336115.
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The ability of G protein-coupled receptors (GPCRs) to initiate complex cascades of cellular signaling is governed by the sequential coupling of three main transducer proteins, G protein, GPCR kinase (GRK), and β-arrestin. Mounting evidence indicates these transducers all have distinct conformational preferences and binding modes. However, interrogating each transducer’s mechanism of interaction with GPCRs has been complicated by the interplay of transducer-mediated signaling events. For example, GRK-mediated receptor phosphorylation recruits and induces conformational changes in β-arrestin, which facilitates coupling to the GPCR transmembrane core. Here we compare the allosteric interactions of G proteins and β-arrestins with GPCRs’ transmembrane cores by using the enzyme sortase to ligate a synthetic phosphorylated peptide onto the carboxyl terminus of three different receptors. Phosphopeptide ligation onto the β2-adrenergic receptor (β2AR) allows stabilization of a high-affinity receptor active state by β-arrestin1, permitting us to define elements in the β2AR and β-arrestin1 that contribute to the receptor transmembrane core interaction. Interestingly, ligation of the identical phosphopeptide onto the β2AR, the muscarinic acetylcholine receptor 2 and the μ-opioid receptor reveals that the ability of β-arrestin1 to enhance agonist binding relative to G protein differs substantially among receptors. Furthermore, strong allosteric coupling of β-arrestin1 correlates with its ability to attenuate, or “desensitize,” G protein activation in vitro. Sortase ligation thus provides a versatile method to introduce complex, defined phosphorylation patterns into GPCRs, and analogous strategies could be applied to other classes of posttranslationally modified proteins. These homogeneously phosphorylated GPCRs provide an innovative means to systematically study receptor–transducer interactions.
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Fessart, Delphine, May Simaan i Stéphane A. Laporte. "c-Src Regulates Clathrin Adapter Protein 2 Interaction with β-Arrestin and the Angiotensin II Type 1 Receptor during Clathrin- Mediated Internalization". Molecular Endocrinology 19, nr 2 (1.02.2005): 491–503. http://dx.doi.org/10.1210/me.2004-0246.
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Abstract β-Arrestins are multifunctional adapters involved in the internalization and signaling of G protein-coupled receptors (GPCRs). They target receptors to clathrin-coated pits (CCPs) through binding with clathrin and clathrin adapter 2 (AP-2) complex. They also act as transducers of signaling by recruiting c-Src kinase to certain GPCRs. Here we sought to determine whether c-Src regulates the recruitment of AP-2 to β-arrestin and the angiotensin II (Ang II) type 1 receptor (AT1R) during internalization. We show that the agonist stimulation of native AT1R in vascular smooth muscle cells (VSMCs) induces the formation of an endogenous complex containing c-Src, β-arrestins and AP-2. In vitro studies using coimmunoprecipitation experiments and a yeast three-hybrid assay reveal that c-Src stabilizes the agonist-independent association between β-arrestin2 and the β-subunit of AP-2 independently of the kinase activity of c-Src. However, although c-Src expression promoted the rapid dissociation of AP-2 from both β-arrestin and AT1R after receptor stimulation, a kinase-inactive mutant of c-Src failed to induce the dissociation of AP-2 from the agonist-occupied receptor. Thus, the consequence of c-Src in regulating the dissociation of AP-2 from the receptor was also examined on the internalization of AT1R by depleting c-Src in human embryonic kidney (HEK) 293 cells using a small interfering RNA strategy. Experiments in c-Src depleted cells reveal that AT1R remained mostly colocalized with AP-2 at the plasma membrane after Ang II stimulation, consistent with the observed delay in receptor internalization. Moreover, coimmunoprecipitation experiments in c-Src depleted HEK 293 cells and VSMCs showed an increased association of AP-2 to the agonist-occupied AT1R and β-arrestin, respectively. Together, our results support a role for c-Src in regulating the dissociation of AP-2 from agonist-occupied AT1R and β-arrestin during the clathrin-mediated internalization of receptors and suggest a novel function for c-Src kinase in the internalization of AT1R.
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Grotegut, Chad A., Liping Feng, Lan Mao, R. Phillips Heine, Amy P. Murtha i Howard A. Rockman. "β-Arrestin mediates oxytocin receptor signaling, which regulates uterine contractility and cellular migration". American Journal of Physiology-Endocrinology and Metabolism 300, nr 3 (marzec 2011): E468—E477. http://dx.doi.org/10.1152/ajpendo.00390.2010.
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Desensitization of the oxytocin receptor (OXTR) in the setting of prolonged oxytocin exposure may lead to dysfunctional labor, which increases the risk for cesarean delivery, and uterine atony, which may result in postpartum hemorrhage. The molecular mechanism for OXTR desensitization is through the agonist-mediated recruitment of the multifunctional protein β-arrestin. In addition to its desensitizing function, β-arrestins have recently been shown to simultaneously activate downstream signaling. We tested whether oxytocin stimulation promotes β-arrestin-mediated OXTR desensitization in vivo and activates β-arrestin-mediated mitogen-activated protein kinase (MAPK) growth signaling. Uterine muscle strips isolated from wild-type mice exhibited diminished uterine contractility following repeated exposure to oxytocin, whereas uterine muscle strips from β-arrestin-1 and β-arrestin-2 knockout mice showed no desensitization. Utilizing siRNA knockdown of β-arrestin-1 and β-arrestin-2 in HEK-293 cells expressing the OXTR, we demonstrated oxytocin-mediated MAPK signaling that was dependent on β-arrestin-1 and β-arrestin-2. Wild-type and β-arrestin-1 and β-arrestin-2 knockout mice receiving intravenous oxytocin also demonstrated oxytocin-mediated MAPK signaling that was dependent on β-arrestin-1 and β-arrestin-2. Finally, to test the significance of β-arrestin-mediated signaling from the OXTR, HEK-293 cells expressing the OXTR showed β-arrestin-dependent proliferation in a cell migration assay following oxytocin treatment. In conclusion, β-arrestin is a multifunctional scaffold protein that mediates both desensitization of the OXTR, leading to decreases in uterine contractility, and MAPK growth signaling following stimulation by oxytocin. The development of unique OXTR ligands that prevent receptor desensitization may be a novel approach in the treatment of adverse clinical events secondary to prolonged oxytocin therapy.
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Neill, Jimmy D., L. Wayne Duck, Lois C. Musgrove i Jeffrey C. Sellers. "Potential Regulatory Roles for G Protein-Coupled Receptor Kinases and β-Arrestins in Gonadotropin-Releasing Hormone Receptor Signaling*". Endocrinology 139, nr 4 (1.04.1998): 1781–88. http://dx.doi.org/10.1210/endo.139.4.5868.
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Abstract GnRH stimulates gonadotropin secretion, which desensitizes unless the releasing hormone is secreted or administered in a pulsatile fashion. The mechanism of desensitization is unknown, but as the GnRH receptor is G protein coupled, it might involve G protein-coupled receptor kinases (GRKs). Such kinases phosphorylate the intracellular regions of seven-transmembrane receptors, permitting β-arrestin to bind, which prevents the receptor from activating G proteins. Here, we tested the effect of GRKs and β-arrestins on GnRH-induced inositol trisphosphate (IP3) production in COS cells transfected with the GnRH receptor complementary DNA. GRK2, -3, and -6 overexpression inhibited IP3 production by 50–75% during the 30 sec of GnRH treatment. Coexpression of GRK2 and β-arrestin-2 suppressed GnRH-induced IP3 production more than that of either alone. Immunocytochemical staining of rat anterior pituitary revealed that all cells expressed GRK2, -3, and -6; all cells also expressed theβ -arrestins. Western blots on cytosolic extracts of rat pituitaries revealed the presence of GRK2/3 and β-arrestin-1 and -2. The expression of GRKs and β-arrestins by gonadotropes and their inhibition of GnRH-stimulated IP3 production in COS-1 cells expressing the GnRH receptor suggest a potential regulatory role for the GRK/β arrestin paradigm in GnRH receptor signaling.
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Van Lith, Lambertus H. C., Julia Oosterom, Andrea Van Elsas i Guido J. R. Zaman. "C5a-Stimulated Recruitment of β-Arrestin2 to the Nonsignaling 7-Transmembrane Decoy Receptor C5L2". Journal of Biomolecular Screening 14, nr 9 (29.07.2009): 1067–75. http://dx.doi.org/10.1177/1087057109341407.
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C5L2 (or GPR77) is a high-affinity receptor for the complement fragment C5a and its desarginated product, C5a-desArg. Unlike the classical C5a receptor CD88, C5L2 does not couple to intracellular G-protein-signaling pathways but is thought to function as a decoy receptor. The authors show that stimulation of C5L2 with C5a and C5a-desArg induces redistribution of green fluorescent protein—labeled β-arrestin2 to cytoplasmic vesicles. C3a and C3a-desArg were inactive in the β-arrestin translocation assay. Direct interaction of ligand-stimulated C5L2 with β-arrestin was confirmed using a novel β-galactosidase fragment complementation assay. In this assay, C5L2 was labeled with a mutationally altered peptide fragment of β-galactosidase, whereas β-arrestin2 was labeled with a corresponding deletion mutant of the enzyme. Stable transfection of the modified C5L2 and subsequent stimulation with C5a or C5a-desArg restored β-galactosidase activity in a dose-dependent manner. The subnanomolar potency of β-arrestin coupling in the β-galactosidase fragment complementation assay is in agreement with the affinity of the receptor-ligand interaction. C5L2 is the first example of a 7-transmembrane decoy receptor that couples to β-arrestin in a ligand-dependent manner. This observation supports the notion that G-protein-signaling and β-arrestin coupling can be 2 separate activities of 7-transmembrane receptors. Furthermore, the β-arrestin assays described in this article provide methods of screening for selective C5L2 modulators. ( Journal of Biomolecular Screening 2009:1067-1075)
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Miranda, Connie Jaqueline, Nicole Fernandez, Nader Kamel, Daniel Turner, Del Benzenhafer, Susan N. Bolch, Jacob T. Andring, Robert McKenna i W. Clay Smith. "An arrestin-1 surface opposite of its interface with photoactivated rhodopsin engages with enolase-1". Journal of Biological Chemistry 295, nr 19 (1.04.2020): 6498–508. http://dx.doi.org/10.1074/jbc.ra120.013043.
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Arrestin-1 is the arrestin family member responsible for inactivation of the G protein–coupled receptor rhodopsin in photoreceptors. Arrestin-1 is also well-known to interact with additional protein partners and to affect other signaling cascades beyond phototransduction. In this study, we investigated one of these alternative arrestin-1 binding partners, the glycolysis enzyme enolase-1, to map the molecular contact sites between these two proteins and investigate how the binding of arrestin-1 affects the catalytic activity of enolase-1. Using fluorescence quench protection of strategically placed fluorophores on the arrestin-1 surface, we observed that arrestin-1 primarily engages enolase-1 along a surface that is opposite of the side of arrestin-1 that binds photoactivated rhodopsin. Using this information, we developed a molecular model of the arrestin-1–enolase-1 complex, which was validated by targeted substitutions of charge-pair interactions. Finally, we identified the likely source of arrestin's modulation of enolase-1 catalysis, showing that selective substitution of two amino acids in arrestin-1 can completely remove its effect on enolase-1 activity while still remaining bound to enolase-1. These findings open up opportunities for examining the functional effects of arrestin-1 on enolase-1 activity in photoreceptors and their surrounding cells.
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Gurevich, Vsevolod V., i Eugenia V. Gurevich. "Solo vs Chorus: Monomers and Oligomers of Arrestin Proteins". International Journal of Molecular Sciences 23, nr 13 (29.06.2022): 7253. http://dx.doi.org/10.3390/ijms23137253.
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Three out of four subtypes of arrestin proteins expressed in mammals self-associate, each forming oligomers of a distinct kind. Monomers and oligomers have different subcellular localization and distinct biological functions. Here we summarize existing evidence regarding arrestin oligomerization and discuss specific functions of monomeric and oligomeric forms, although too few of the latter are known. The data on arrestins highlight biological importance of oligomerization of signaling proteins. Distinct modes of oligomerization might be an important contributing factor to the functional differences among highly homologous members of the arrestin protein family.
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Morales, Paula, Marta Bruix i M. Angeles Jiménez. "Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides". International Journal of Molecular Sciences 21, nr 21 (30.10.2020): 8111. http://dx.doi.org/10.3390/ijms21218111.
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Activation of the cannabinoid CB1 receptor induces different cellular signaling cascades through coupling to different effector proteins (G-proteins and β-arrestins), triggering numerous therapeutic effects. Conformational changes and rearrangements at the intracellular domain of this GPCR receptor that accompany ligand binding dictate the signaling pathways. The GPCR-binding interface for G proteins has been extensively studied, whereas β-arrestin/GPCR complexes are still poorly understood. To gain knowledge in this direction, we designed peptides that mimic the motifs involved in the putative interacting region: β-arrestin1 finger loop and the transmembrane helix 7-helix 8 (TMH7-H8) elbow located at the intracellular side of the CB1 receptor. According to circular dichroism and NMR data, these peptides form a native-like, helical conformation and interact with each other in aqueous solution, in the presence of trifluoroethanol, and using zwitterionic detergent micelles as membrane mimics. These results increase our understanding of the binding mode of β-arrestin and CB1 receptor and validate minimalist approaches to structurally comprehend complex protein systems.
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Holliday, Nicholas D., Birgitte Holst, Elena A. Rodionova, Thue W. Schwartz i Helen M. Cox. "Importance of Constitutive Activity and Arrestin-Independent Mechanisms for Intracellular Trafficking of the Ghrelin Receptor". Molecular Endocrinology 21, nr 12 (1.12.2007): 3100–3112. http://dx.doi.org/10.1210/me.2007-0254.
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Abstract The ghrelin receptor (GhrelinR) and its related orphan GPR39 each display constitutive signaling, but only GhrelinRs undergo basal internalization. Here we investigate these differences by considering the roles of the C tail receptor domains for constitutive internalization and activity. Furthermore the interaction between phosphorylated receptors and β-arrestin adaptor proteins has been examined. Replacement of the FLAG-tagged GhrelinR C tail with the equivalent GPR39 domain (GhR-39 chimera) preserved Gq signaling. However in contrast to the GhrelinR, GhR-39 receptors exhibited no basal and substantially decreased agonist-induced internalization in transiently transfected HEK293 cells. Internalized GhrelinR and GhR-39 were predominantly localized to recycling compartments, identified with transferrin and the monomeric G proteins Rab5 and Rab11. Both the inverse agonist [d-Arg1, d-Phe5, d-Trp7,9, Leu11] substance P and a naturally occurring mutant GhrelinR (A204E) with eliminated constitutive activity inhibited basal GhrelinR internalization. Surprisingly, we found that noninternalizing GPR39 was highly phosphorylated and that basal and agonist-induced phosphorylation of the GhR-39 chimera was elevated compared with GhrelinRs. Moreover, basal GhrelinR endocytosis occurred without significant phosphorylation, and it was not prevented by cotransfection of a dominant-negative β-arrestin1(319–418) fragment or by expression in β-arrestin1/2 double-knockout mouse embryonic fibroblasts. In contrast, agonist-stimulated GhrelinRs recruited the clathrin adaptor green fluorescent protein-tagged β-arrestin2 to endosomes, coincident with increased receptor phosphorylation. Thus, GhrelinR internalization to recycling compartments depends on C-terminal motifs and constitutive activity, but the high levels of GPR39 phosphorylation, and of the GhR-39 chimera, are not sufficient to drive endocytosis. In addition, basal GhrelinR internalization occurs independently of β-arrestins.
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Parameswaran, Narayanan, Babu Gonipeta, Sitaram Parvataneni, Nandakumar Packiriswamy i Deepika Sharma. "β-arrestin-1 negatively regulates inflammatory response to polymicrobial sepsis in mice (110.11)". Journal of Immunology 186, nr 1_Supplement (1.04.2011): 110.11. http://dx.doi.org/10.4049/jimmunol.186.supp.110.11.
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Abstract β-arrestins are scaffolding proteins that regulate a number of receptor signaling pathways including Toll-like receptors. We recently demonstrated that mice lacking either β-arrestin-1 or β-arrestin-2 are protected from lipopolysaccharide-induced lethality and have a markedly reduced inflammatory response. To assess the role of β-arrestin-1 in a clinically relevant model of sepsis, we subjected wild type and β-arrestin-1 knockout mice to cecal-ligation and puncture (CLP) to mimick septic peritonitis and polymicrobial sepsis. Surprisingly, we found that, mortality of β-arrestin-1 knockout mice was significantly enhanced compared to the wild type mice after CLP. Consistent with lethality, β-arrestin-1 knockout mice had markedly elevated inflammatory cytokine levels in the plasma, peritoneal cavity, and bronchoalveolar fluid. Enhanced systemic inflammatory response of β-arrestin-1 knockout mice was associated with significantly enhanced infiltration of immune cells into the peritoneal cavity after induction of septic peritonitis. Together, these results demonstrate that, contrary to its role in lipolysaccharide-TLR4 signaling in vivo, β-arrestin-1 is a negative regulator of inflammation induced by polymicrobial sepsis and that the phenotype of the mice may be related to a potentially aberrant immune response from excess infiltration of immune cells. These results also suggest that the role of β-arrestin-1 in this model is likely independent of its role in TLR4 signaling in vivo.
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Sterne-Marr, R., V. V. Gurevich, P. Goldsmith, R. C. Bodine, C. Sanders, L. A. Donoso i J. L. Benovic. "Polypeptide variants of beta-arrestin and arrestin3". Journal of Biological Chemistry 268, nr 21 (lipiec 1993): 15640–48. http://dx.doi.org/10.1016/s0021-9258(18)82304-3.
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Frederick, Terra J., i Stephen D. Miller. "Arresting autoimmunity by blocking β-arrestin 1". Nature Immunology 8, nr 8 (sierpień 2007): 791–92. http://dx.doi.org/10.1038/ni0807-791.
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Padilla, Benjamin E., Graeme S. Cottrell, Dirk Roosterman, Stella Pikios, Laurent Muller, Martin Steinhoff i Nigel W. Bunnett. "Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and β-arrestins". Journal of Cell Biology 179, nr 5 (26.11.2007): 981–97. http://dx.doi.org/10.1083/jcb.200704053.
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Although cell surface metalloendopeptidases degrade neuropeptides in the extracellular fluid to terminate signaling, the function of peptidases in endosomes is unclear. We report that isoforms of endothelin-converting enzyme-1 (ECE-1a–d) are present in early endosomes, where they degrade neuropeptides and regulate post-endocytic sorting of receptors. Calcitonin gene-related peptide (CGRP) co-internalizes with calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), β-arrestin2, and ECE-1 to early endosomes, where ECE-1 degrades CGRP. CGRP degradation promotes CLR/RAMP1 recycling and β-arrestin2 redistribution to the cytosol. ECE-1 inhibition or knockdown traps CLR/RAMP1 and β-arrestin2 in endosomes and inhibits CLR/RAMP1 recycling and resensitization, whereas ECE-1 overexpression has the opposite effect. ECE-1 does not regulate either the resensitization of receptors for peptides that are not ECE-1 substrates (e.g., angiotensin II), or the recycling of the bradykinin B2 receptor, which transiently interacts with β-arrestins. We propose a mechanism by which endosomal ECE-1 degrades neuropeptides in endosomes to disrupt the peptide/receptor/β-arrestin complex, freeing internalized receptors from β-arrestins and promoting recycling and resensitization.
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Oakley, Robert H., J. Alberto Olivares-Reyes, Christine C. Hudson, Fabiola Flores-Vega, Frank M. Dautzenberg i Richard L. Hauger. "Carboxyl-terminal and intracellular loop sites for CRF1 receptor phosphorylation and β-arrestin-2 recruitment: a mechanism regulating stress and anxiety responses". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 293, nr 1 (lipiec 2007): R209—R222. http://dx.doi.org/10.1152/ajpregu.00099.2006.
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The primary goal was to test the hypothesis that agonist-induced corticotropin-releasing factor type 1 (CRF1) receptor phosphorylation is required for β-arrestins to translocate from cytosol to the cell membrane. We also sought to determine the relative importance to β-arrestin recruitment of motifs in the CRF1 receptor carboxyl terminus and third intracellular loop. β-Arrestin-2 translocated significantly more rapidly than β-arrestin-1 to agonist-activated membrane CRF1 receptors in multiple cell lines. Although CRF1 receptors internalized with agonist treatment, neither arrestin isoform trafficked with the receptor inside the cell, indicating that CRF1 receptor-arrestin complexes dissociate at or near the cell membrane. Both arrestin and clathrin-dependent mechanisms were involved in CRF1 receptor internalization. To investigate molecular determinants mediating the robust β-arrestin-2-CRF1 receptor interaction, mutagenesis was performed to remove potential G protein-coupled receptor kinase phosphorylation sites. Truncating the CRF1 receptor carboxyl terminus at serine-386 greatly reduced agonist-dependent phosphorylation but only partially impaired β-arrestin-2 recruitment. Removal of a serine/threonine cluster in the third intracellular loop also significantly reduced CRF1 receptor phosphorylation but did not alter β-arrestin-2 recruitment. Phosphorylation was abolished in a CRF1 receptor possessing both mutations. Surprisingly, this mutant still recruited β-arrestin-2. These mutations did not alter membrane expression or cAMP signaling of CRF1 receptors. Our data reveal the involvement of at least the following two distinct receptor regions in β-arrestin-2 recruitment: 1) a carboxyl-terminal motif in which serine/threonine residues must be phosphorylated and 2) an intracellular loop motif configured by agonist-induced changes in CRF1 receptor conformation. Deficient β-arrestin-2-CRF1 receptor interactions could contribute to the pathophysiology of affective disorders by inducing excessive CRF1 receptor signaling.
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Cleghorn, Whitney M., Kevin M. Branch, Seunghyi Kook, Christopher Arnette, Nada Bulus, Roy Zent, Irina Kaverina, Eugenia V. Gurevich, Alissa M. Weaver i Vsevolod V. Gurevich. "Arrestins regulate cell spreading and motility via focal adhesion dynamics". Molecular Biology of the Cell 26, nr 4 (15.02.2015): 622–35. http://dx.doi.org/10.1091/mbc.e14-02-0740.
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Focal adhesions (FAs) play a key role in cell attachment, and their timely disassembly is required for cell motility. Both microtubule-dependent targeting and recruitment of clathrin are critical for FA disassembly. Here we identify nonvisual arrestins as molecular links between microtubules and clathrin. Cells lacking both nonvisual arrestins showed excessive spreading on fibronectin and poly-d-lysine, increased adhesion, and reduced motility. The absence of arrestins greatly increases the size and lifespan of FAs, indicating that arrestins are necessary for rapid FA turnover. In nocodazole washout assays, FAs in arrestin-deficient cells were unresponsive to disassociation or regrowth of microtubules, suggesting that arrestins are necessary for microtubule targeting–dependent FA disassembly. Clathrin exhibited decreased dynamics near FA in arrestin-deficient cells. In contrast to wild-type arrestins, mutants deficient in clathrin binding did not rescue the phenotype. Collectively the data indicate that arrestins are key regulators of FA disassembly linking microtubules and clathrin.