scholarly journals Endo-lysosomal sorting of G-protein-coupled receptors by ubiquitin: Diverse pathways for G-protein-coupled receptor destruction and beyond

Traffic ◽  
2018 ◽  
Vol 20 (2) ◽  
pp. 101-109 ◽  
Author(s):  
Michael R. Dores ◽  
JoAnn Trejo
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled Receptor ◽  
Lysosomal Sorting ◽  
G Protein Coupled

scholarly journals G Protein-coupled Receptor Kinases of the GRK4 Protein Subfamily Phosphorylate Inactive G Protein-coupled Receptors (GPCRs)

2015 ◽  
Vol 290 (17) ◽  
pp. 10775-10790 ◽  
Author(s):  
Lingyong Li ◽  
Kristoff T. Homan ◽  
Sergey A. Vishnivetskiy ◽  
Aashish Manglik ◽  
John J. G. Tesmer ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled Receptor ◽  
Receptor Kinases ◽  
G Protein Coupled

scholarly journals Identification of a Conserved, Orphan G Protein-Coupled Receptor Required for Efficient Pathogen Clearance in Caenorhabditis elegans

2019 ◽  
Vol 87 (4) ◽  
Author(s):  
Alexandra Anderson ◽  
Yee Lian Chew ◽  
William Schafer ◽  
Rachel McMullan
Keyword(s):  
Caenorhabditis Elegans ◽  
Immune Responses ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled Receptor ◽  
Content Type ◽  
C Elegans ◽  
Host Immune Responses ◽  
Pathogen Clearance ◽  
G Protein Coupled

ABSTRACT G protein-coupled receptors contribute to host defense across the animal kingdom, transducing many signals involved in both vertebrate and invertebrate immune responses. While it has become well established that the nematode worm Caenorhabditis elegans triggers innate immune responses following infection with numerous bacterial, fungal, and viral pathogens, the mechanisms by which C. elegans recognizes these pathogens have remained somewhat more elusive. C. elegans G protein-coupled receptors have been implicated in recognizing pathogen-associated damage and activating downstream host immune responses. Here we identify and characterize a novel G protein-coupled receptor required to regulate the C. elegans response to infection with Microbacterium nematophilum. We show that this receptor, which we designate pathogen clearance-defective receptor 1 (PCDR-1), is required for efficient pathogen clearance following infection. PCDR-1 acts upstream of multiple G proteins, including the C. elegans Gαq ortholog, EGL-30, in rectal epithelial cells to promote pathogen clearance via a novel mechanism.

scholarly journals Acute loss of Cell–Cell Communication Caused by G Protein–coupled Receptors: A Critical Role for c-Src

1998 ◽  
Vol 140 (5) ◽  
pp. 1199-1209 ◽  
Author(s):  
Friso R. Postma ◽  
Trudi Hengeveld ◽  
Jacqueline Alblas ◽  
Ben N.G. Giepmans ◽  
Gerben C.M. Zondag ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Gap Junction ◽  
G Protein ◽  
Critical Role ◽  
Cell Communication ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled Receptor ◽  
Junction Protein ◽  
G Protein Coupled ◽  
Cell Cell

Gap junctions mediate cell–cell communication in almost all tissues, but little is known about their regulation by physiological stimuli. Using a novel single-electrode technique, together with dye coupling studies, we show that in cells expressing gap junction protein connexin43, cell–cell communication is rapidly disrupted by G protein–coupled receptor agonists, notably lysophosphatidic acid, thrombin, and neuropeptides. In the continuous presence of agonist, junctional communication fully recovers within 1–2 h of receptor stimulation. In contrast, a desensitization-defective G protein–coupled receptor mediates prolonged uncoupling, indicating that recovery of communication is controlled, at least in part, by receptor desensitization. Agonist-induced gap junction closure consistently follows inositol lipid breakdown and membrane depolarization and coincides with Rho-mediated cytoskeletal remodeling. However, we find that gap junction closure is independent of Ca2+, protein kinase C, mitogen-activated protein kinase, or membrane potential, and requires neither Rho nor Ras activation. Gap junction closure is prevented by tyrphostins, by dominant-negative c-Src, and in Src-deficient cells. Thus, G protein–coupled receptors use a Src tyrosine kinase pathway to transiently inhibit connexin43-based cell–cell communication.

scholarly journals Down-Regulation of Protease-activated Receptor-1 Is Regulated by Sorting Nexin 1

2002 ◽  
Vol 13 (6) ◽  
pp. 1965-1976 ◽  
Author(s):  
Yingjie Wang ◽  
Yixing Zhou ◽  
Katalin Szabo ◽  
Carol Renfrew Haft ◽  
JoAnn Trejo
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
Down Regulation ◽  
Sorting Nexin ◽  
Early Endosomes ◽  
Lysosomal Sorting ◽  
Protease Activated Receptor 1 ◽  
Phox Homology ◽  
G Protein Coupled ◽  
Sorting Nexin 1

Degradation or “down-regulation” of protease-activated receptor-1 (PAR1), a G protein-coupled receptor for thrombin, is critical for termination of receptor signaling. Toward understanding the molecular mechanisms by which activated PAR1 is internalized, sorted to lysosomes, and degraded, we investigated whether PAR1 interacted with sorting nexin 1 (SNX1). SNX1 is a membrane-associated protein that functions in lysosomal sorting of the epidermal growth factor receptor. In vitro biochemical binding assays revealed a specific interaction between a glutathione S-transferase fusion of SNX1 and PAR1. In HeLa cells, activated PAR1 colocalized with endogenous SNX1 and coimmunoprecipitated SNX1. SNX1 contains a phox homology domain predicted to bind phosphatidylinositol-3-phosphate and a C-terminal coiled-coil region. To assess SNX1 function, we examined the effects of SNX1 deletion mutants on PAR1 trafficking. Neither the N terminus nor phox homology domain of SNX1 affected PAR1 trafficking. By contrast, overexpression of SNX1 C-terminal domain markedly inhibited agonist-induced degradation of PAR1, whereas internalization remained virtually intact. Immunofluorescence microscopy studies revealed substantial PAR1 accumulation in an early endosome antigen-1-positive compartment in agonist-treated cells expressing SNX1 C terminus. By contrast, lysosome-associated membrane protein-1 distribution was unperturbed. Together, these findings strongly suggest a role for SNX1 in sorting of PAR1 from early endosomes to lysosomes. Moreover, this study provides the first example of a protein involved in lysosomal sorting of a G protein-coupled receptor in mammalian cells.

scholarly journals Constitutive, Basal, and β-Alanine-Mediated Activation of the Human Mas-Related G Protein-Coupled Receptor D Induces Release of the Inflammatory Cytokine IL-6 and Is Dependent on NF-κB Signaling

2021 ◽  
Vol 22 (24) ◽  
pp. 13254
Author(s):  
Rohit Arora ◽  
Kenny M. Van Theemsche ◽  
Samuel Van Remoortel ◽  
Dirk J. Snyders ◽  
Alain J. Labro ◽  
...  
Keyword(s):  
G Protein ◽  
Inflammatory Mediator ◽  
Dynamic Range ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled Receptor ◽  
Screening Assay ◽  
Cardiovascular Tissue ◽  
Basal Activity ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) have emerged as key players in regulating (patho)physiological processes, including inflammation. Members of the Mas-related G protein coupled receptors (MRGPRs), a subfamily of GPCRs, are largely expressed by sensory neurons and known to modulate itch and pain. Several members of MRGPRs are also expressed in mast cells, macrophages, and in cardiovascular tissue, linking them to pseudo-allergic drug reactions and suggesting a pivotal role in the cardiovascular system. However, involvement of the human Mas-related G-protein coupled receptor D (MRGPRD) in the regulation of the inflammatory mediator interleukin 6 (IL-6) has not been demonstrated to date. By stimulating human MRGPRD-expressing HeLa cells with the agonist β-alanine, we observed a release of IL-6. β-alanine-induced signaling through MRGPRD was investigated further by probing downstream signaling effectors along the Gαq/Phospholipase C (PLC) pathway, which results in an IkB kinases (IKK)-mediated canonical activation of nuclear factor kappa-B (NF-κB) and stimulation of IL-6 release. This IL-6 release could be blocked by a Gαq inhibitor (YM-254890), an IKK complex inhibitor (IKK-16), and partly by a PLC inhibitor (U-73122). Additionally, we investigated the constitutive (ligand-independent) and basal activity of MRGPRD and concluded that the observed basal activity of MRGPRD is dependent on the presence of fetal bovine serum (FBS) in the culture medium. Consequently, the dynamic range for IL-6 detection as an assay for β-alanine-mediated activation of MRGPRD is substantially increased by culturing the cells in FBS free medium before treatment. Overall, the observation that MRGPRD mediates the release of IL-6 in an in vitro system, hints at a role as an inflammatory mediator and supports the notion that IL-6 can be used as a marker for MRGPRD activation in an in vitro drug screening assay.

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