Changes in G Protein-coupled Receptor Sorting Protein Affinity Regulate Postendocytic Targeting of G Protein-coupled Receptors

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.

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

The Journal of Cell Biology ◽

10.1083/jcb.140.5.1199 ◽

1998 ◽

Vol 140 (5) ◽

pp. 1199-1209 ◽

Cited By ~ 84

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.

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Bombyx neuropeptide G protein-coupled receptor A14 and A15 are two functional G protein-coupled receptors for CCHamide neuropeptides

Insect Biochemistry and Molecular Biology ◽

10.1016/j.ibmb.2021.103553 ◽

2021 ◽

Vol 131 ◽

pp. 103553

Author(s):

Yanan Tian ◽

Chaohui Jiang ◽

Yi Pan ◽

Zhiqiang Guo ◽

Weiwei Wang ◽

...

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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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

International Journal of Molecular Sciences ◽

10.3390/ijms222413254 ◽

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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The Drosophila G-protein-coupled receptor kinase homologue Gprk2 is required for egg morphogenesis

Development ◽

10.1242/dev.124.13.2591 ◽

1997 ◽

Vol 124 (13) ◽

pp. 2591-2602 ◽

Cited By ~ 2

Author(s):

L.E. Schneider ◽

A.C. Spradling

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Follicle Cells ◽

Protein Signaling ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

Receptor Kinases ◽

A Cell ◽

External Signals ◽

G Protein Coupled

G protein signaling is a widely utilized form of extracellular communication that is mediated by a family of serpentine receptors containing seven transmembrane domains. In sensory neurons, cardiac muscle and other tissues, G protein-coupled receptors are desensitized through phosphorylation by a family of kinases, the G protein-coupled receptor kinases (GRKs). Desensitization allows a cell to decrease its response to a given signal, in the continued presence of that signal. We have identified a Drosophila mutant, gprk2(6936) that disrupts expression of a putative member of the GRK family, the G protein-coupled receptor kinase 2 gene (Gprk2). This mutation affects Gprk2 gene expression in the ovaries and renders mutant females sterile. The mutant eggs contain defects in several anterior eggshell structures that are produced by specific subsets of migratory follicle cells. In addition, rare eggs that become fertilized display gross defects in embryogenesis. These observations suggest that developmental signals transduced by G protein-coupled receptors are regulated by receptor phosphorylation. Based on the known functions of G protein-coupled receptor kinases, we speculate that receptor desensitization assists cells that are migrating or undergoing shape changes to respond rapidly to changing external signals.

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Docosahexaenoic acid, G protein–coupled receptors, and melanoma: is G protein–coupled receptor 40 a potential therapeutic target?

Journal of Surgical Research ◽

10.1016/j.jss.2014.01.037 ◽

2014 ◽

Vol 188 (2) ◽

pp. 451-458 ◽

Cited By ~ 13

Author(s):

Deepika Nehra ◽

Amy H. Pan ◽

Hau D. Le ◽

Erica M. Fallon ◽

Sarah J. Carlson ◽

...

Keyword(s):

Docosahexaenoic Acid ◽

G Protein ◽

Therapeutic Target ◽

G Protein Coupled Receptors ◽

G Protein Coupled Receptor ◽

Potential Therapeutic Target ◽

G Protein Coupled

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Regulation of G protein-coupled receptor endocytosis by ARF6 GTP-binding proteins

Biochemistry and Cell Biology ◽

10.1139/o04-113 ◽

2004 ◽

Vol 82 (6) ◽

pp. 610-617 ◽

Cited By ~ 20

Author(s):

Audrey Claing

Keyword(s):

G Protein ◽

Molecular Mechanisms ◽

G Protein Coupled Receptors ◽

G Protein Coupled Receptor ◽

Adp Ribosylation ◽

Internalization Process ◽

Intracellular Compartments ◽

Broad Variety ◽

Membrane Bound ◽

G Protein Coupled

The function of G protein-coupled receptors is regulated by a broad variety of membrane-bound and intracellular proteins. These act in concert to activate signaling pathways that will lead to the desensitization of activated receptors and, for most receptor types, their trafficking to intracellular compartments. This review focuses mainly on the endocytic pathways used by a G protein-coupled receptor and on the proteins that play an essential role in the regulation of the internalization process, most specifically the ADP-ribosylation factors. This family of proteins has been shown to be important for vesicle trafficking between different cellular membranes. The latest findings regarding the molecular mechanisms that regulate internalization of an agonist-stimulated receptor are presented here. Finally, a perspective on how ARF6 proteins might regulate the internalization process is also proposed.Key words: G protein-coupled receptors, endocytosis, ADP-ribosylation factor.

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