Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Böhm, Stephan; Grady, Eileen F.; Bunnett, Nigel W.

doi:10.1042/bj3220001

Cited by 475 publications

(341 citation statements)

References 227 publications

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“…It has been revealed that putative Ser/Thr phosphorylation sites are present in the cytoplasmic tail of PAFR (51). PKC activation can phosphorylate these residues, resulting in the interaction with ␤-arrestin and uncoupling from the G-protein, leading to the desensitization and receptor internalization (52). This may explain the early phase effect of PDB observed in our study, as the inhibition of PAF-triggered [Ca 2ϩ ] i elevation by PDB could be blocked by pretreatment with BIM, a specific PKC inhibitor.…”

Section: Discussionsupporting

confidence: 62%

Activation Via Multiple Signaling Pathways Induces Down-Regulation of Platelet-Activating Factor Receptors on Human B Lymphocytes

Zhuang

Bastien

Mazer

2000

The Journal of Immunology

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Platelet-activating factor receptor (PAFR) has been identified in B cell lines and primary human B cells, but the regulation of PAFR during B cell activation has not been completely elucidated. In the present study, we have investigated the effects of B cell activation on PAFR binding parameters, PAFR mRNA and PAF-triggered intracellular calcium mobilization. The human B lymphoid cell line LA350 was shown to exhibit high levels of PAFR (48,550 ± 4,310 sites/cell) as determined by radio-ligand binding assay with PAFR antagonist [3H]WEB2086. Treatment with phorbol 12,13-dibutyrate caused a biphasic reduction of PAFR binding. The early phase was inhibited by the protein kinase C inhibitor bisindolylmaleimide I (BIM), whereas the late phase was not blocked by BIM, protein tyrosine kinase inhibitor genistein, or the mitogen-activated protein kinase/extracellular signal-related kinase inhibitor PD98059. However, staurosporine, a broad-spectrum protein kinase inhibitor, completely inhibited the late phase down-regulation. Ionomycin also decreased [3H]WEB2086 binding sites, whereas the combination of PDB and ionomycin induced a greater reduction than either agent alone. Cross-linking of B cell receptor by anti-IgM Ab also induced down-regulation of PAFR, which was abolished by genistein or PD98059, but not by BIM or staurosporine. The decrease in surface PAFR number was closely paralleled by the reduction in PAFR mRNA both in LA350 cells and human tonsillar B cells, and was associated with decreased response to PAF indicated by decreased intracellular calcium mobilization. These data show that multiple signaling pathways are involved in down-regulating PAFR expression during B cell activation and development.

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Section: Discussionsupporting

confidence: 62%

Activation Via Multiple Signaling Pathways Induces Down-Regulation of Platelet-Activating Factor Receptors on Human B Lymphocytes

Zhuang

Bastien

Mazer

2000

The Journal of Immunology

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“…After binding of SDF, CXCR4 is sequestered into early endosomes enabling a rapid recycling of the chemokine receptor after removal of the ligand. In addition to agonistdependent receptor phosphorylation by G-proteincoupled receptor kinases, other kinases like PKC may mediate receptor internalization and desensitization either by directly phosphorylating G-protein-coupled receptors or by the indirect up-regulation of G-proteincoupled receptor kinases [24,25]. For example, rapid internalization of CXCR4 was observed after stimulation of lymphocytes with phorbol esters [14,26].…”

Section: Discussionmentioning

confidence: 99%

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Brühl¹,

Cohen²,

Linder³

et al. 2003

Eur J Immunol

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We have investigated the regulation and function of the chemokine receptor CXCR4 on neutrophils. CXCR4 is hardly detectable on neutrophils in the peripheral blood. However, overnight culture strongly up-regulates CXCR4 expression on the cell surface. The functional activity of CXCR4 on cultured neutrophils was confirmed by stromal cell-derived factor (SDF)-induced migration and up-regulation of the integrins CD11b and CD11c. CXCR4 surface expression on neutrophils but not on lymphocytes and monocytes is rapidly downregulated after stimulation with TNF- § and IFN-+ , resulting in significantly decreased SDFinduced functional responses of neutrophils. In contrast to surface expression, CXCR4 mRNA expression was several-fold increased in cytokine-stimulated neutrophils, suggesting a post-translational regulation. By confocal microscopy we demonstrate that CXCR4 is internalized after stimulation with TNF- § and IFN-+ . b he down-modulation of CXCR4 surface expression in response to TNF- § and IFN-+ was fully reversible after cytokine removal. Further, CXCR4 down-modulation could be completely blocked by hypertonic sucrose and significantly reduced by chlorpromazine indicating the involvement of clathrin-coated pits. Internalization of CXCR4 by cytokines in a cell type-specific manner is a novel and functionally important mechanism of chemokine receptor regulation.

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“…1a) is reminiscent of short-term receptor desensitization (6,7). Receptor desensitization has been extensively studied in the ␤-adrenergic receptor system (6) and has also been described for opioid receptors mostly in terms of the diminishing agonist inhibition of cAMP levels induced by forskolin (2-4).…”

Section: Resultsmentioning

confidence: 99%

“…Desensitization of the -opioid receptor involves agonistdependent phosphorylation of the receptor, most likely by a member of the family of G-coupled receptor protein kinases (GRKs) (4,5). According to this model, upon phosphorylation and uncoupling from the G protein, the receptor is bound to ␤-arrestins and internalized into endosomes, reducing the number of receptors available at the cell surface for further agonist binding (6,7).…”

mentioning

confidence: 99%

A Mitogen-activated Protein Kinase Pathway Is Required for μ-Opioid Receptor Desensitization

Polakiewicz

Schieferl

Dorner

et al. 1998

Journal of Biological Chemistry

129

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The -opioid receptor mediates not only the beneficial painkilling effects of opiates like morphine but also the detrimental effects of chronic exposure such as tolerance and dependence. Different studies have linked tolerance to opioid receptor desensitization. Agonist activation of the -opioid receptor stimulates a mitogenactivated protein kinase (MAPK) activity, but the functional significance of this pathway remains unclear. We have focused on the MAPK signaling cascade to study -opioid receptor desensitization. We report that inhibition of the MAPK pathway blocks desensitization of -opioid receptor signaling as well as the loss of receptor density due to internalization. Our results suggest that a feedback signal emanating from the MAPK cascade is required for -opioid receptor desensitization.Agonists for the -opioid receptor are the therapeutic choice in the management of severe acute and chronic pain despite the potential development of tolerance, dependence, and addiction. The mechanisms of tolerance, defined as the diminishing effect of the drug in response to chronic exposure, are not fully understood. It has been postulated that receptor desensitization and down-regulation could be associated with aspects of tolerance in vivo (1). Opioid receptors undergo homologous desensitization upon continuous or repeated agonist exposure in a fashion similar to other G protein-coupled receptors (GPCR) 1 (2-4). Desensitization of the -opioid receptor involves agonistdependent phosphorylation of the receptor, most likely by a member of the family of G-coupled receptor protein kinases (GRKs) (4, 5). According to this model, upon phosphorylation and uncoupling from the G protein, the receptor is bound to ␤-arrestins and internalized into endosomes, reducing the number of receptors available at the cell surface for further agonist binding (6, 7).Desensitization of the -opioid receptor has been mainly described as the attenuated reduction of forskolin-stimulated cAMP levels in response to the agonist (2-4). However, other signaling pathways might also be desensitized upon prolonged agonist exposure. GPCRs can trigger a G␤␥-mediated activation of a phosphoinositide 3-kinase (PI3K)/Ras-dependent MAPK signaling pathway (8, 9). Opioid receptors stimulate MAPK activity as well, although the components of this signaling cascade have not been fully described (10 -12). In this report we have examined the role of the MAPK (Erk1/2) signaling pathway on -opioid receptor desensitization. This pathway, which involves the activation of a phosphatidylinositol 3-kinase activity as well as Raf and MEK1/2, is essential for -opioid receptor desensitization. EXPERIMENTAL PROCEDURESReagents-[D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]enkephalin (DAMGO), dermorphin, morphine, Met-enkephalin, naloxone, D-Pen 2 ,D-Pen 5 -enkephalin (DPDPE), lysophosphatidic acid (LPA), pertussis toxin, cycloheximide, forskolin, and isobutylmethylxanthine (IBMX) were from Sigma. Wortmannin and LY294002 were from Calbiochem. Antibodies that recognize only the phosphorylated...

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Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Cited by 475 publications

References 227 publications

Activation Via Multiple Signaling Pathways Induces Down-Regulation of Platelet-Activating Factor Receptors on Human B Lymphocytes

Activation Via Multiple Signaling Pathways Induces Down-Regulation of Platelet-Activating Factor Receptors on Human B Lymphocytes

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

A Mitogen-activated Protein Kinase Pathway Is Required for μ-Opioid Receptor Desensitization

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