scholarly journals Multifaceted roles of β-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling

2003 ◽  
Vol 375 (3) ◽  
pp. 503-515 ◽  
Author(s):  
Sudha K. SHENOY ◽  
Robert J. LEFKOWITZ
Keyword(s):  
G Protein ◽  
Receptor Internalization ◽  
Adapter Proteins ◽  
Adapter Protein ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Membrane Spanning ◽  
G Protein Coupled ◽  
Adp Ribosylation Factor

β-Arrestins are cytosolic proteins that bind to activated and phosphorylated G-protein-coupled receptors [7MSRs (seven-membrane-spanning receptors)] and uncouple them from G-protein-mediated second messenger signalling pathways. The binding of β-arrestins to 7MSRs also leads to new signals via activation of MAPKs (mitogen-activated protein kinases) such as JNK3 (c-Jun N-terminal kinase 3), ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPKs. By binding to endocytic proteins [clathrin, AP2 (adapter protein 2), NSF (N-ethylmaleimide-sensitive fusion protein) and ARF6 (ADP-ribosylation factor 6)], β-arrestins also serve as adapters to link the receptors to the cellular trafficking machinery. Agonist-promoted ubiquitination of β-arrestins is a prerequisite for their role in receptor internalization, as well as a determinant of the differing trafficking patterns of distinct classes of receptors. Recently, β-arrestins have also been implicated as playing novel roles in cellular chemotaxis and apoptosis. By virtue of their ability to bind, in a stimulus-dependent fashion, to 7MSRs as well as to different classes of cellular proteins, β-arrestins serve as versatile adapter proteins that regulate the signalling and trafficking of the receptors.

scholarly journals Chemokine Production by G Protein-Coupled Receptor Activation in a Human Mast Cell Line: Roles of Extracellular Signal-Regulated Kinase and NFAT

2000 ◽  
Vol 165 (12) ◽  
pp. 7215-7223 ◽  
Author(s):  
Hydar Ali ◽  
Jasimuddin Ahamed ◽  
Cristina Hernandez-Munain ◽  
Jonathan L. Baron ◽  
Michael S. Krangel ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Line ◽  
G Protein ◽  
Receptor Activation ◽  
Human Mast Cell ◽  
Chemokine Production ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mast Cell Line ◽  
G Protein Coupled

G-protein–coupled receptor signaling in Syk-deficient neutrophils and mast cells

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 4155-4163 ◽  
Author(s):  
Attila Mócsai ◽  
Hong Zhang ◽  
Zoltán Jakus ◽  
Jiro Kitaura ◽  
Toshiaki Kawakami ◽  
...  
Keyword(s):  
Mast Cells ◽  
Map Kinase ◽  
G Protein ◽  
Intracellular Signaling ◽  
P38 Map Kinase ◽  
Inflammatory Protein ◽  
Chemokine Signaling ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

Abstract The Syk tyrosine kinase is essential for immunoreceptor and multiple integrin functions as well as being implicated in signaling from G-protein–coupled receptors (GPCR) in cell lines, transfection systems, and pharmacologic studies. In contrast, using Syk-deficient primary cells, we show here that Syk does not play a major functional role in chemoattractant/chemokine signaling in neutrophils and mast cells. syk−/− neutrophils showed normal respiratory burst and degranulation in response to the bacterial peptide formyl-Met-Leu-Phe (fMLP). The migration of neutrophils toward fMLP was similarly not affected by the syk−/−mutation. fMLP initiated normal Ca2+-signal, activation of the extracellular signal-related kinase (ERK) and p38 mitogen–activated protein (MAP) kinase cascades, and polymerization of cellular actin in the absence of Syk.syk−/− and wild-type neutrophils also responded similarly to LTB4, C5a, and the chemokines macrophage inflammatory protein-1 (MIP-1)α or MIP-2, both in functional assays and in intracellular signaling mechanisms. Furthermore, bone marrow–derived syk−/− mast cells showed normal activation of the Akt, ERK, and p38 MAP kinase pathways when stimulated by the GPCR ligand adenosine. We conclude that, in contrast to previous reports, Syk does not play a major role in GPCR signaling.

scholarly journals Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors

2019 ◽  
Author(s):  
Jeffrey S. Smith ◽  
Thomas F. Pack ◽  
Asuka Inoue ◽  
Claudia Lee ◽  
Xinyu Xiong ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Environmental Signals ◽  
Extracellular Signal Regulated Kinase ◽  
Intracellular Signals ◽  
Extracellular Signal ◽  
Extracellular Stimuli ◽  
Protein Isoform ◽  
Sense And Respond ◽  
G Protein Coupled

SummaryG-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct Gα proteins, such as Gαs, Gαi, Gαq or Gα12/13, as well as β-arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of Gα proteins to directly interact with β-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gαi protein family members and β-arrestin. Gαi:β-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gαi:β-arrestin scaffolds enhances our understanding of GPCR signalling.

scholarly journals Different cAMP sources are critically involved in G protein–coupled receptor CRHR1 signaling

2016 ◽  
Vol 214 (2) ◽  
pp. 181-195 ◽  
Author(s):  
Carolina Inda ◽  
Paula A. dos Santos Claro ◽  
Juan J. Bonfiglio ◽  
Sergio A. Senin ◽  
Giuseppina Maccarrone ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cyclic Amp ◽  
G Protein ◽  
Adenylyl Cyclases ◽  
Alternative Source ◽  
Soluble Adenylyl Cyclase ◽  
Extracellular Signal Regulated Kinase ◽  
Signaling Mechanisms ◽  
Extracellular Signal ◽  
G Protein Coupled

Corticotropin-releasing hormone receptor 1 (CRHR1) activates G protein–dependent and internalization-dependent signaling mechanisms. Here, we report that the cyclic AMP (cAMP) response of CRHR1 in physiologically relevant scenarios engages separate cAMP sources, involving the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). cAMP produced by tmACs and sAC is required for the acute phase of extracellular signal regulated kinase 1/2 activation triggered by CRH-stimulated CRHR1, but only sAC activity is essential for the sustained internalization-dependent phase. Thus, different cAMP sources are involved in different signaling mechanisms. Examination of the cAMP response revealed that CRH-activated CRHR1 generates cAMP after endocytosis. Characterizing CRHR1 signaling uncovered a specific link between CRH-activated CRHR1, sAC, and endosome-based signaling. We provide evidence of sAC being involved in an endocytosis-dependent cAMP response, strengthening the emerging model of GPCR signaling in which the cAMP response does not occur exclusively at the plasma membrane and introducing the notion of sAC as an alternative source of cAMP.

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