Long-Term Morphine Treatment Enhances Proteasome-Dependent Degradation of Gβ in Human Neuroblastoma SH-SY5Y Cells: Correlation with Onset of Adenylate Cyclase Sensitization

Moulédous, Lionel; Neasta, Jérémie; Uttenweiler-Joseph, Sandrine; Stella, Alexandre; Matondo, Mariette; Corbani, Maïthé; Monsarrat, Bernard; Meunier, Jean‐Claude

doi:10.1124/mol.105.013391

Cited by 34 publications

(33 citation statements)

References 45 publications

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“…Such a CCT "jamming" may eventually cause cell death, similarly to that in rods expressing the dominant negative PhLP mutant (19). Given that the ubiquitin-proteasome system plays a critical role in intracellular degradation of both Gprotein βγ-complexes and unfolded Gβ subunits (20,21), it is likely that the bulk of Gβ 1 synthetized in Gγ 1 −/− rods is eventually targeted to proteasomes, either directly or following a stage of CCT association (Fig. 1D, Lower).…”

Section: Resultsmentioning

confidence: 99%

“…Given that the ubiquitin-proteasome system plays a critical role in intracellular degradation of unfolded Gβ subunits (20,21), we assessed the functional status of this system in Gγ 1 −/− and Gγ 1 −/− Gβ 1 +/− mice by crossing them with transgenic mice expressing an in vivo reporter of proteasome activity, Ub G76V -GFP (a fusion of ubiquitin with GFP containing a G76V mutation in the linker) (23). The lifetime of this reporter in healthy cells is short, whereas its intracellular accumulation is indicative of proteasomal insufficiency (24).…”

Section: Resultsmentioning

confidence: 99%

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Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Inherited retinal degenerations, caused by mutations in over 100 individual genes, affect approximately 2 million people worldwide. Many of the underlying mutations cause protein misfolding or mistargeting in affected photoreceptors. This places an increased burden on the protein folding and degradation machinery, which may trigger cell death. We analyzed how these cellular functions are affected in degenerating rods of the transducin γ-subunit (Gγ 1 ) knockout mouse. These rods produce large amounts of transducin β-subunit (Gβ 1 ), which cannot fold without Gγ 1 and undergoes intracellular proteolysis instead of forming a transducin βγ-subunit complex. Our data revealed that the most critical pathobiological factor leading to photoreceptor cell death in these animals is insufficient capacity of proteasomes to process abnormally large amounts of misfolded protein. A decrease in the Gβ 1 production in Gγ 1 knockout rods resulted in a significant reduction in proteasomal overload and caused a striking reversal of photoreceptor degeneration. We further demonstrated that a similar proteasomal overload takes place in photoreceptors of other mutant mice where retinal degeneration has been ascribed to protein mistargeting or misfolding, but not in mice whose photoreceptor degenerate as a result of abnormal phototransduction. These results establish the prominence of proteasomal insufficiency across multiple degenerative diseases of the retina, thereby positioning proteasomes as a promising therapeutic target for treating these debilitating conditions. neurodegenerative diseases | protein degradation

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…3A). Similarly, FLNA interacts with MOR in the neuroblastoma SH-SY5Y cell line that stably expresses the T7-tagged MOR (SH-SY5Y-MOR) (31,32) (Fig. 3B).…”

Section: Resultsmentioning

confidence: 99%

“…BxPC-3 cells were stably transfected with either the human T7-tagged wild-type sst2 or mutated I 65 Y 66 V 67 sst2, and pools were selected using 400 g/ml G-418. SH-SY5Y cells were stably transfected with the T7-tagged MOR receptor, as described previously (32), and provided by L. mouledous.…”

Section: Methodsmentioning

confidence: 99%

A Switch of G Protein-Coupled Receptor Binding Preference from Phosphoinositide 3-Kinase (PI3K)–p85 to Filamin A Negatively Controls the PI3K Pathway

Najib

Saint-Laurent

Estève

et al. 2012

Molecular and Cellular Biology

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Frequent oncogenic alterations occur in the phosphoinositide 3-kinase (PI3K) pathway, urging identification of novel negative controls. We previously reported an original mechanism for restraining PI3K activity, controlled by the somatostatin G proteincoupled receptor (GPCR) sst2 and involving a ligand-regulated interaction between sst2 with the PI3K regulatory p85 subunit. We here identify the scaffolding protein filamin A (FLNA) as a critical player regulating the dynamic of this complex. A preexisting sst2-p85 complex, which was shown to account for a significant basal PI3K activity in the absence of ligand, is disrupted upon sst2 activation. FLNA was here identified as a competitor of p85 for direct binding to two juxtaposed sites on sst2. Switching of GPCR binding preference from p85 toward FLNA is determined by changes in the tyrosine phosphorylation of p85-and FLNA-binding sites on sst2 upon activation. It results in the disruption of the sst2-p85 complex and the subsequent inhibition of PI3K. Knocking down FLNA expression, or abrogating FLNA recruitment to sst2, reversed the inhibition of PI3K and of tumor growth induced by sst2. Importantly, we report that this FLNA inhibitory control on PI3K can be generalized to another GPCR, the mu opioid receptor, thereby providing an unprecedented mechanism underlying GPCR-negative control on PI3K.

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“…From consideration of the 6-h data, it is evident that the proteasome inhibitor was able to prevent the loss of agonist-induced signaling downstream of the receptor in the absence of an increase in receptor binding sites. It was reported recently that chronic morphine treatment decreased the level of G␣ i2 and G␣ i3 in Chinese hamster ovary cells expressing the -opioid receptor (Xu et al, 2005) and G␣ i2 , G␣ i3 , G␤ 1 , and G␤ 2 in human neuroblastoma SHSY5Y cells endogenously expressing -and ␦-opioid receptors (Mouledous et al, 2005). If DADL activation of the ␦-opioid receptor has a similar effect on these G proteins in DOR-expressing HEK 293 cells and if the proteasome is involved in the agonist-induced decrease in G protein expression, as it is in SHSY5Y cells (Mouledous et al, 2005), the proteasome inhibitor may be able to partially prevent the loss of agonist stimulation of […”

Section: Discussionmentioning

confidence: 99%

Inhibition of Agonist-Induced Down-Regulation of the δ-Opioid Receptor with a Proteasome Inhibitor Attenuates Opioid Tolerance in Human Embryonic Kidney 293 Cells

Yadav

Chaturvedi²,

Howells³

2006

J Pharmacol Exp Ther

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This study was designed to test the hypothesis that inhibition of agonist-induced ␦-receptor down-regulation would block the development of opioid tolerance in a cell-based model. A human embryonic kidney 293 cell line was established that expressed an epitope-tagged ␦-opioid receptor (DOR). Opioid receptors are members of the G protein-coupled receptor (GPCR) superfamily and mediate the effects of endogenous opioid peptides in the central, peripheral and enteric nervous systems. Opioid receptors are also the molecular targets of opioid drugs, such as morphine. Opioids are the most powerful analgesic drugs available currently and are the treatment of choice for the management of moderate to severe pain (McQuay, 1999). Adverse effects, including respiratory depression, nausea, and constipation, affect their use, and protracted opioid therapy leads to drug tolerance and physical dependence. Tolerance is defined as a loss of efficacy following repeated administration, and it is common for patients on long-term opioid therapy to increase their dosage (Sittl et al., 2005). Adaptive changes at the molecular, cellular, synaptic, and neural network level are induced by habitual use of opioid analgesics, although much remains to be learned about the mechanisms involved in the adaptive plasticity (Bailey and Connor, 2005). Opioid receptors, like other GPCRs, are subject to agonist-induced desensitization and internalization, involving phosphorylation of receptors by G protein receptor kinases and association with ␤-arrestins (Lefkowitz and Shenoy, 2005), whereas chronic exposure leads to receptor down-regulation, which involves proteolysis of the receptors. Both desensitization and down-regulation are probably involved in opioid tolerance. It has been shown that -and ␦-opioid receptors are phosphorylated by G protein receptor kinases after agonist treatment (Pei et al., 1995) and are sequestered by endocytosis in an arrestin-and dynamin-dependent process via clathrin-coated pits (Chu et al., 1997). Morphine analgesia is enhanced in knockout mice

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Long-Term Morphine Treatment Enhances Proteasome-Dependent Degradation of Gβ in Human Neuroblastoma SH-SY5Y Cells: Correlation with Onset of Adenylate Cyclase Sensitization

Cited by 34 publications

References 45 publications

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

A Switch of G Protein-Coupled Receptor Binding Preference from Phosphoinositide 3-Kinase (PI3K)–p85 to Filamin A Negatively Controls the PI3K Pathway

Inhibition of Agonist-Induced Down-Regulation of the δ-Opioid Receptor with a Proteasome Inhibitor Attenuates Opioid Tolerance in Human Embryonic Kidney 293 Cells

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