Function of non-visual arrestins in signaling and endocytosis of the gastrin-releasing peptide receptor (GRP receptor)

Schümann, Michael; Nakagawa, Tomoo; Mantey, Samuel A.; Howell, Brian W.; Jensen, Robert T.

doi:10.1016/j.bcp.2007.11.022

Cited by 8 publications

(9 citation statements)

References 58 publications

(73 reference statements)

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“…75 Subsequently, activation leads to GRPR C-terminal exposure and arrestin dependent regulation for incoming nanocages. 76,77 Once such signals have been communicated, the first and most significant event is the formation of positive curvature toward cytosol in the plasma membrane near the receptor. 42,44 Membrane curving would reflect a postbinding scenario as evident in TEM images (Figure 9).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Bombesin Peptide Conjugated Gold Nanocages Internalize via Clathrin Mediated Endocytosis

Suresh¹,

Zambre²,

Chanda³

et al. 2014

Bioconjugate Chem.

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The nature of interaction and mechanism of internalization of receptor-avid peptide nanoparticles with cells is not yet completely understood. This article describes the cellular internalization mechanism and intracellular trafficking of peptide conjugated receptor targeted porous Gold nanocages (AuNCs) in cancer cells. We synthesized and characterized a library of AuNCs conjugated with bombesin (BBN) peptide. Evidence of selective affinity of AuNC-BBN toward gastrin releasing peptide receptors (GRPR) was obtained using radiolabeled competitive cell binding assay. Endocytic mechanism was investigated using cell inhibitor studies and monitored using optical and transmission electron microscopy (TEM). Results show AuNC-BBN uptake in PC3 cells is mediated by clathrin mediated endocytosis (CME). Indeed, in the presence of CME inhibitors, AuNC-BBN uptake in cells is reduced up to 84%. TEM images further confirm CME characteristic clathrin coated pits and lysosomal release of AuNCs. These results demonstrate that peptide ligands conjugated to the surface of nanoparticles maintain their target specificity. This bolsters the case for peptide robustness and its persisting functionality in intracellular vehicular delivery systems.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Bombesin Peptide Conjugated Gold Nanocages Internalize via Clathrin Mediated Endocytosis

Suresh¹,

Zambre²,

Chanda³

et al. 2014

Bioconjugate Chem.

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“…This study also noted a conserved conformational change that occurs upon activation of both arrestin-2 and -3 and involves increased protease accessibility of the region between amino acids 180 and 250 in both isoforms, consistent with increased flexibility of this region upon arrestin activation. Furthermore, different trafficking routes for agonist-activated gastrin-releasing peptide receptor (GRP-R)-arrestin-2 and GRP-R-arrestin-3 complexes were reported49. Arrestin-3 internalizes with GRP-R to endosomes, whereas arrestin-2 dissociates from the GRP-R near the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of Arrestin-3 Reveals the Basis of the Difference in Receptor Binding Between Two Non-visual Subtypes

Zhan

Giménez

Gurevich

et al. 2011

Journal of Molecular Biology

194

266

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Arrestins are multi-functional proteins that regulate signaling and trafficking of the majority of G protein-coupled receptors (GPCRs), as well as sub-cellular localization and activity of many other signaling proteins. Here we report the first crystal structure of arrestin-3, solved at 3.0Å. Arrestin-3 is an elongated two-domain molecule with the overall fold and key inter-domain interactions that hold free protein in the basal conformation similar to the other subtypes. Arrestin-3 is the least selective member of the family, binding wide variety of GPCRs with high affinity and demonstrating lower preference for active phosphorylated forms of the receptors. In contrast to the other three arrestins, part of the receptor-binding surface in the arrestin-3 C-domain does not form a contiguous β-sheet, consistent with increased flexibility. By swapping the corresponding elements between arrestin-2 and -3 we show that the presence of this loose structure correlates with reduced arrestin selectivity for activated receptor, consistent with a conformational change in this β-sheet upon receptor binding.

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“…This is in contrast to a number of other groups of synthetic Bn receptor ligands including various desMet 14 Bn amides, desMet 14 Bn alkylamides, desMet 14 Bn esters and various ϕ13−14 Bn pseudopeptides, that can function as antagonist at the GRP receptor in some species, but function as a partial agonist in others [92,93] or that function as antagonist at the hGRP receptor but function as partial agonists at hNMBR receptors [18,73]. Because agonists that function as full agonists are rapidly internalized by Bn receptor-containing cells [29,55,80] the potent agonists described in this study with full efficacy for activating the receptor, should be especially useful for studies that require internalizations of the ligand, such as receptor mediated cytotoxicity studies [77]. …”

Section: Discussionmentioning

confidence: 99%

Pharmacology and selectivity of various natural and synthetic bombesin related peptide agonists for human and rat bombesin receptors differs

et al. 2011

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The mammalian bombesin (Bn)-receptor family[gastrin-releasing peptide-receptor(GRPR-receptor), neuromedin B-receptor(NMB-receptor)], their natural ligands,GRP/NMB, as well as the related orphan-receptor,BRS-3, are widely-distributed, and frequently overexpressed by tumors. There is increased interest in agonists for this receptor family to explore their roles in physiological/pathophysiological processes, and for receptor-imaging/cytotoxicity in tumors. However, there is minimal data on human pharmacology of Bn-receptor agonists and most results are based on nonhuman receptor studies, particular rodent-receptors, which with other receptors frequently differ from human-receptors. To address this issue we compared hNMB/GRP-receptor affinities and potencies/efficacies of cell-activation(assessing phospholipase C activity) for 24 putative Bn-agonists(12-natural,12-synthetic) in four different cells with these receptors, containing native-receptors or receptors expressed at physiological densities, and compared the results to native rat-GRP-receptor-containing cells-(AR42J–cells) or rat-NMB-receptor cells(C6-glioblastoma cells). There were close correlations(r=0.92–99,p<0.0001) between their affinities/potencies for the two hGRP- or hNMB-receptor cells. Twelve analogues had high affinities(≤ 1 nM) for hGRP-receptor with 15 selective for it(greatest=GRP,NMC), 8 had high affinity/potencies for hNMB-receptors and 4 were selective for it. Only synthetic Bn-analogues containing β−alanine11 had high affinity for hBRS-3, but t also had high affinities/potencies for all GRP-/hNMB-receptor cells. There was no correlation between affinities for human-GRP-receptors and rat-GRP-receptors(r=0.131,p=0.54), but hNMB-receptor results correlated with rat-NMB-receptor(r=0.71, p<0.0001). These results elucidate the human- and rat-GRP-receptor pharmacophore for agonists differ markedly,whereas they do not for NMB-receptors, therefore potential GRP-receptor agonists for human studies(such as Bn-receptor-imaging/cytotoxicity) must be assessed on human-Bn-receptors. The current study provides affinities/potencies on a large number of potential agonists that might be useful for human studies.

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Function of non-visual arrestins in signaling and endocytosis of the gastrin-releasing peptide receptor (GRP receptor)

Cited by 8 publications

References 58 publications

Bombesin Peptide Conjugated Gold Nanocages Internalize via Clathrin Mediated Endocytosis

Bombesin Peptide Conjugated Gold Nanocages Internalize via Clathrin Mediated Endocytosis

Crystal Structure of Arrestin-3 Reveals the Basis of the Difference in Receptor Binding Between Two Non-visual Subtypes

Pharmacology and selectivity of various natural and synthetic bombesin related peptide agonists for human and rat bombesin receptors differs

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