Ubiquitin-Mediated Proteasome Activity Is Required for Agonist-Induced Endocytosis of GluRs

Patrick, Gentry N.; Bingol, Baris; Weld, Holli A.; Schuman, Erin M.

doi:10.1016/j.cub.2003.10.028

Cited by 191 publications

(159 citation statements)

References 37 publications

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“…Instead, we have shown that augmented reduction of fear-potentiated startle and reversal of GluR1 increase by DCS were blocked by proteasome inhibitors. The rationale is that NMDA-induced AMPA receptor endocytosis requires ubiquitin-mediated proteasome activity (Patrick et al, 2003;Colledge et al, 2003). We first tested this idea in the amygdala slices.…”

Section: Discussionmentioning

confidence: 99%

“…However, when DCS was applied 5 min before and during LFS, fEPSP declined to the baseline level at 2 h after TS . In cultured hippocampal neurons, NMDA-induced receptor internalization was blocked by proteasome inhibitors, indicating the regulation of receptor trafficking by ubiquitin-proteasome system (UPS) (Patrick et al, 2003;Colledge et al, 2003). We tested whether proteasome inhibitors affected DCS-induced facilitation of depotentiation.…”

Section: In Vitro Studiesmentioning

confidence: 99%

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Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

Mao

Lin

Gean

2008

Neuropsychopharmacol

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D-Cycloserine (DCS) has been shown to facilitate extinction of conditioned fear in rats and to improve fear reduction of social phobia and fear of heights in human studies. Here, we investigate the mechanism of DCS effect by measuring internalized GluR1 and GluR2 using cell-surface biotinylation techniques. DCS selectively increased NMDA receptor-mediated synaptic response without affecting AMPA receptor-mediated synaptic response. Low-frequency stimulation (LFS) when applied in the presence of DCS induced GluR1 and GluR2 internalization in the amygdala slices. Proteasome inhibitors block DCS facilitation of LFS-induced depotentiation and a reduction in surface levels of GluR1 and GluR2. Furthermore, DCS in combination with LFS reduced cellular levels of PSD-95 and synapse-associated protein 97 (SAP97), which were also blocked by proteasome inhibitors. In the in vivo experiments, DCS-induced reduction of fearpotentiated startle and reversal of conditioning-induced increase in surface expression of GluR1 were blocked by proteasome inhibitors. DCS-treated rats fail to exhibit reinstatement after US-alone presentations. These results suggest that DCS facilitates receptor internalization in the presence of extinction training, resulting in augmented reduction of startle potentiation.

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Section: Discussionmentioning

confidence: 99%

Section: In Vitro Studiesmentioning

confidence: 99%

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

Mao

Lin

Gean

2008

Neuropsychopharmacol

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“…The initial studies showed that AMPA-induced internalization of AMPAR was abolished by the proteasome inhibitor MG132, but no ubiquitination of AMPAR subunits was observed at that time (Patrick et al, 2003). Additional studies suggested that this internalization is due to a reduced stabilization of AMPA receptors into synaptic sites as a result of PSD-95 degradation (Colledge et al, 2003).…”

Section: Role Of Ups In Nervous Systemmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

117

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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“…In mammalian hippocampal neurons, treatment with the proteasome inhibitor MG132 blocks agonist-induced endocytosis of AMPA-type glutamate receptors (Patrick et al 2003). Also, NMDA-induced AMPA receptor internalization is prevented by the application of the proteasome inhibitor.…”

Section: Postsynaptic Roles Of the Uppmentioning

confidence: 99%

The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

131

123

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Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wideranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons.

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Ubiquitin-Mediated Proteasome Activity Is Required for Agonist-Induced Endocytosis of GluRs

Cited by 191 publications

References 37 publications

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

The ubiquitin-proteasome pathway and synaptic plasticity

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