Rat beta-adrenergic receptor kinases 1 and 2 in mouse neuroblastoma X rat glioma NG 10845 hybrid cells

Schulz, Karin; Müller, Stefan; Belke-Louis, Georg; Schulz, Rüdiger

doi:10.1016/s0006-2952(97)00380-8

Cited by 6 publications

(3 citation statements)

References 19 publications

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“…Crossmodal modulation between molecular compounds modulating polymerization and depolymerization of microtubules and βAR modulated signaling may be critically implicated in glioma initiation, promotion, progression, invasion, and metastasis [93]. NG 108-15 rat neuroblastoma cells express βARK isotypes 1 and 2 mRNA and exhibit Gβγ-dependent phosphorylation of rhodopsin and agonist-bound delta opioid receptor, recapitulating effects mediated by βAR activation in non-transformed cells [94,95]. Glioma cells may exhibit differential kinetics of βAR desensitization compared with non-malignantly-transformed cells.…”

Section: Mechanisms Underlying Desensitization Of β Adrenergic Receptmentioning

confidence: 99%

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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Neoplastically transformed astrocytes express functionally active cell surface β adrenergic receptors (βARs). Treatment of glioma models in vitro and in vivo with β adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, β adrenergic agonists generally reduce cellular proliferation. However, treatment with β adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. β adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with β adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate βagonists to represent an enhancer of bevacizumab. The antiangiogenic effects of β adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. β adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the β adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the β adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the β adrenergic receptor induces its phosphorylation by β adrenergic receptor kinase (βARK), rendering it a suitable substrate for alternate binding by β arrestins 1 or 2. The binding of a β arrestin to βARK phosphorylated βAR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the βAR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, βAR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the β adrenergic receptor favoring β arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.

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Section: Mechanisms Underlying Desensitization Of β Adrenergic Receptmentioning

confidence: 99%

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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“…The critical function of G␤␥ for the process of internalization becomes clear when phosducin-EGFP is included. Phosducin is known to compete with GRK2/3 for G␤␥, thereby protecting the receptor from phosphorylation (Mü ller et al, 1997;Schulz et al, 1998a) and internalization (Schulz et al, 1999a,b). The very close location of fluorescent receptors and GRKs in microdomains of the membrane may account for the observed cointernalization.…”

Section: Discussionmentioning

confidence: 99%

Visualizing Preference of G Protein-Coupled Receptor Kinase 3 for the Process of κ-Opioid Receptor Sequestration

Schulz¹,

Wehmeyer²,

Schulz³

2002

Mol Pharmacol

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G protein-coupled receptor kinases (GRKs) phosphorylate opioid receptors, which eventually results in receptor sequestration. With respect to -opioid receptors, it is known that internalization occurs in a species-specific manner. That is, the agonist-occupied human -receptors will sequester whereas murine receptors fail to do so. This investigation concentrates on the internalization of -opioid receptors, employing laser scanning microscopy as a major technique to examine receptor internalization in living cells. For this reason, we fused green fluorescence protein to -receptors, and DsRed-fluorescent protein to GRK2 and GRK3. All fusion proteins retained their biologic activities. Permanent cell lines (HEK 293, were transfected to express either green fluorescent -receptors or to coexpress the tagged receptor and a specific GRKDsRed construct. The localization of fluorescent receptors and GRKs was monitored by confocal microscopy before and after opioid exposure of transfected cells. Activation of the murine -receptors triggers rapid translocation of tagged GRKs toward the cell membrane, but receptor internalization was not observed. The agonist-occupied human -receptor also causes translocation of GRK2-and GRK3-DsRed, which was followed by the formation of vesicles carrying the green fluorescent -receptors. Moreover, the green fluorescent vesicles consistently harbour red fluorescent GRK2 and GRK3, respectively. The phenomenon of -receptor internalization as well as cointernalization of GRKs is blocked by phosducin, indicating a critical role of G protein-␤␥ subunits for -receptor sequestration. Comparing the effect of over-expressed GRK2 and GRK3 on sequestration of -receptors, we conclude that GRK3 more strongly induces -receptor internalization than GRK2.

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“…GRK4, GRK5 and GRK6 lack this Gbetagamma subunit binding domain but use direct PIP 2 binding and/or covalent lipid modification with palmitate to reside primarily at the plasma membrane (49). Although there is no current evidence indicating the specificity of GRKs for opioid receptor subtypes, a number of studies in heterologous expression systems have shown that MOPR can be phosphorylated by GRK2 (48, 50), GRK3 (51,52) and GRK6 (52), DOPR can be phosphorylated by GRK2 (53, 54), GRK3 (51), and GRK5 (55) and KOPR by GRK2 (56) or GRK3 (57). However, in the case of KOPR, a study showed that agonist mediated phosphorylation of human KOPR was blocked by expression of a dominant negative GRK2 mutant, whereas rat KOPR was not phosphorylated by the same agonist even in the presence of GRK2 or GRK3 (58).…”

Section: Proteins That Modulate Opioid Receptor Signalingmentioning

confidence: 99%

Modulation of opioid receptor function by protein-protein interactions

Alfaras-Melainis

Gomes²,

Rozenfeld³

et al. 2009

Front Biosci

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Opioid receptors, MORP, DORP and KORP, belong to the family A of G protein coupled receptors (GPCR), and have been found to modulate a large number of physiological functions, including mood, stress, appetite, nociception and immune responses. Exogenously applied opioid alkaloids produce analgesia, hedonia and addiction. Addiction is linked to alterations in function and responsiveness of all three opioid receptors in the brain. Over the last few years, a large number of studies identified protein-protein interactions that play an essential role in opioid receptor function and responsiveness. Here, we summarize interactions shown to affect receptor biogenesis and trafficking, as well as those affecting signal transduction events following receptor activation. This article also examines protein interactions modulating the rate of receptor endocytosis and degradation, events that play a major role in opiate analgesia. Like several other GPCRs, opioid receptors may form homo or heterodimers. The last part of this review summarizes recent knowledge on proteins known to affect opioid receptor dimerization.

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Rat beta-adrenergic receptor kinases 1 and 2 in mouse neuroblastoma X rat glioma NG 10845 hybrid cells

Cited by 6 publications

References 19 publications

Visualizing Preference of G Protein-Coupled Receptor Kinase 3 for the Process of κ-Opioid Receptor Sequestration

Modulation of opioid receptor function by protein-protein interactions

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