Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PSD-95 is a major scaffolding protein of the postsynaptic density, tethering NMDA- and AMPA-type glutamate receptors to signaling proteins and the neuronal cytoskeleton. Here we show that PSD-95 is regulated by the ubiquitin-proteasome pathway. PSD-95 interacts with and is ubiquitinated by the E3 ligase Mdm2. In response to NMDA receptor activation, PSD-95 is ubiquitinated and rapidly removed from synaptic sites by proteasome-dependent degradation. Mutations that block PSD-95 ubiquitination prevent NMDA-induced AMPA receptor endocytosis. Likewise, proteasome inhibitors prevent NMDA-induced AMPA receptor internalization and synaptically induced long-term depression. This is consistent with the notion that PSD-95 levels are an important determinant of AMPA receptor number at the synapse. These data suggest that ubiquitination of PSD-95 through an Mdm2-mediated pathway is critical in regulating AMPA receptor surface expression during synaptic plasticity.
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PMID:Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. 1464 82

Recent studies documenting a role for local protein synthesis in synaptic plasticity have lead to interest in the opposing process, protein degradation, as a potential regulator of synaptic function. The ubiquitin-conjugation system identifies, modifies, and delivers proteins to the proteasome for degradation. We found that both the proteasome and ubiquitin are present in the soma and dendrites of hippocampal neurons. As the trafficking of glutamate receptors (GluRs) is thought to underlie some forms of synaptic plasticity, we examined whether blocking proteasome activity affects the agonist-induced internalization of GluRs in cultured hippocampal neurons. Treatment with the glutamate agonist AMPA induced a robust internalization of GluRs. In contrast, brief pretreatment with proteasome inhibitors completely prevented the internalization of GluRs. To distinguish between a role for the proteasome and a possible diminution of the free ubiquitin pool, we expressed a chain elongation defective ubiquitin mutant (UbK48R), which causes premature termination of polyubiquitin chains but, importantly, can serve as a substrate for mono-ubiquitin-dependent processes. Expression of K48R in neurons severely diminished AMPA-induced internalization establishing a role for the proteasome. These data demonstrate the acute (e.g., minutes) regulation of synaptic function by the ubiquitin-proteasome pathway in mammalian neurons.
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PMID:Ubiquitin-mediated proteasome activity is required for agonist-induced endocytosis of GluRs. 1465 97

Amyloid-beta (Abeta) has been implicated in memory loss and disruption of synaptic plasticity observed in early-stage Alzheimer's disease. Recently, it has been shown that soluble Abeta oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of Abeta in the regulation of synaptic structure and function. Postsynaptic density-95 (PSD-95) is a postsynaptic scaffolding protein that plays a critical role in synaptic plasticity and the stabilization of AMPA (AMPARs) and NMDA (NMDARs) receptors at synapses. Here, we show that exposure of cultured cortical neurons to soluble oligomers of Abeta(1-40) reduces PSD-95 protein levels in a dose- and time-dependent manner and that the Abeta1(1-40)-dependent decrease in PSD-95 requires NMDAR activity. We also show that the decrease in PSD-95 requires cyclin-dependent kinase 5 activity and involves the proteasome pathway. Immunostaining analysis of cortical cultured neurons revealed that Abeta treatment induces concomitant decreases in PSD-95 at synapses and in the surface expression of the AMPAR glutamate receptor subunit 2. Together, these data suggest a novel pathway by which Abeta triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.
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PMID:Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. 1631 6

The entorhinal cortex (EC) serves as a gateway to the hippocampus and plays a pivotal role in memory processing in the brain. Superficial layers of the EC convey the cortical input projections to the hippocampus, whereas deep layers of the EC relay hippocampal output projections back to the superficial layers of the EC or to other cortical regions. Whereas the EC expresses long-term potentiation (LTP) and depression (LTD), the underlying cellular and molecular mechanisms have not been determined. Because the axons of the stellate neurons in layer II of the EC form the perforant path that innervates the dentate gyrus granule cells of the hippocampus, we studied the mechanisms underlying the long-term plasticity in identified stellate neurons. Application of high-frequency stimulation (100 Hz for 1 s, repeated 3 times at an interval of 10 s) or forskolin (50 microM) failed to induce significant changes in synaptic strength, whereas application of pairing (presynaptic stimulation at 0.33 Hz paired with postsynaptic depolarization from -60 to -10 mV for 5 min) or low-frequency stimulation (LFS, 1 Hz for 15 min) paradigm-induced LTD. Pairing- or LFS-induced LTDs were N-methyl-D-aspartate receptor-dependent and occluded each other suggesting that they have the similar cellular mechanism. Pairing-induced LTD required the activity of calcineurin and involved AMPA receptor endocytosis that required the function of ubiquitin-proteasome system. Our study provides a cellular mechanism that might in part explain the role of the EC in memory.
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PMID:Long-term depression in identified stellate neurons of juvenile rat entorhinal cortex. 1713 66

The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression.
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PMID:Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. 1720 82

The mitochondria have several important functions in the cell. A mitochondrial dysfunction causes an abatement in ATP production, oxidative damage and the induction of apoptosis, all of which are involved in the pathogenesis of numerous disorders. This review focuses on mitochondrial dysfunctions and discusses their consequences and potential roles in the pathomechanism of neurodegenerative disorders. Other pathogenetic factors are also briefly surveyed. The second part of the review deals with the kynurenine metabolic pathway, its alterations and their potential association with cellular energy impairment in certain neurodegenerative diseases. During energy production, most of the O(2) consumed by the mitochondria is reduced fully to water, but 1-2% of the O(2) is reduced incompletely to give the superoxide anion (O(2)(-)). If the function of one or more respiratory chain complexes is impaired for any reason, the enhanced production of free radicals further worsens the mitochondrial function by causing oxidative damage to macromolecules, and by opening the mitochondrial permeability transition pores thereby inducing apoptosis. These high-conductance pores offer a pathway which can open in response to certain stimuli, leading to the induction of the cells' own suicide program. This program plays an essential role in regulating growth and development, in the differentiation of immune cells, and in the elimination of abnormal cells from the organism. Both failure and exaggeration of apoptosis in a human body can lead to disease. The increasing amount of superoxide anions can react with nitric oxide to yield the highly toxic peroxynitrite anion, which can destroy cellular macromolecules. The roles of oxidative, nitrative and nitrosative damage are discussed. Senescence is accompanied by a higher degree of reactive oxygen species production, and by diminished functions of the endoplasmic reticulum and the proteasome system, which are responsible for maintenance of the normal protein homeostasis of the cell. In the event of a dysfunction of the endoplasmic reticulum, unfolded proteins aggregate in it, forming potentially toxic deposits which tend to be resistant to degradation. Cells possess adaptive mechanisms with which to avoid the accumulation of incorrectly folded proteins. These involve molecular chaperones that fold proteins correctly, and the ubiquitin proteasome system which degrades misfolded, unwanted proteins. Both the endoplasmic reticulum and the ubiquitin proteasome system fulfill cellular protein quality control functions. The kynurenine system: Tryptophan is metabolized via several pathways, the main one being the kynurenine pathway. A central compound of the pathway is kynurenine (KYN), which can be metabolized in two separate ways: one branch furnishing kynurenic acid, and the other 3-hydroxykynurenine and quinolinic acid, the precursors of NAD. An important feature of kynurenic acid is the fact that it is one of the few known endogenous excitatory amino acid receptor blockers with a broad spectrum of antagonistic properties in supraphysiological concentrations. One of its recently confirmed sites of action is the alpha7-nicotinic acetylcholine receptor and interestingly, a more recently identified one is a higher affinity positive modulatory binding site at the AMPA receptor. Kynurenic acid has proven to be neuroprotective in several experimental settings. On the other hand, quinolinic acid is a specific agonist at the N-methyl-d-aspartate receptors, and a potent neurotoxin with an additional and marked free radical-producing property. There are a number of neurodegenerative disorders whose pathogenesis has been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism. These changes may disturb normal brain function and can add to the pathomechanisms of the diseases. In certain disorders, there is a quinolinic acid overproduction, while in others the alterations in brain kynurenic acid levels are more pronounced. A more precise knowledge of these alterations yields a basis for getting better therapeutic possibilities. The last part of the review discusses metabolic disturbances and changes in the kynurenine metabolic pathway in Parkinson's, Alzheimer's and Huntington's diseases.
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PMID:Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. 1746 70

Ubiquitination regulates the degradation, membrane trafficking, and transcription of proteins. At mammalian synapses, the ubiquitin-proteasome system (UPS) influences synaptic transmission and plasticity. Nicotine also has the ability to affect synaptic function via mechanisms that remain partially unknown. We found that nicotine, at concentrations achieved by smokers, reduced proteasomal activity, produced accumulation of ubiquitinated synaptic proteins, and increased total protein levels. In particular, a 24 h exposure to nicotine decreased proteasome-dependent degradation of the alpha7 nicotinic acetylcholine receptor (nAChR) subunit, as indicated by the accumulation of ubiquitinated alpha7. The same nicotine treatment increased the levels of the AMPA glutamate receptor subunit GluR1, the NMDA receptor subunit NR2A, the metabotropic receptor mGluR1alpha, the plasticity factor Homer-1A, and the scaffolding postsynaptic density protein PSD-95, whereas the levels of another scaffolding protein, Shank, were reduced. These changes were associated with an inhibition of proteasomal chymotrypsin-like activity by nicotine. The nAChR antagonist mecamylamine was only partially able to block the effects of nicotine on the UPS, indicating that nAChR activation does not completely explain nicotine-induced inhibition of proteasomal catalytic activity. A competition binding assay suggested a direct interaction between nicotine and the 20S proteasome. These results suggest that the UPS might participate in nicotine-dependent synaptic plasticity.
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PMID:Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity. 1789 22

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 fear-potentiated 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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PMID:Augmentation of fear extinction by D-cycloserine is blocked by proteasome inhibitors. 1836 37

Extensive work has shown that activation of the cAMP-dependent protein kinase A (PKA) is crucial for long-term depression (LTD) of synaptic transmission in the hippocampus, a phenomenon that is thought to be involved in memory formation. Here we studied the role of an alternative target of cAMP, the exchange protein factor directly activated by cyclic AMP (Epac). We show that pharmacological activation of Epac by the selective agonist 8-(4-chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT) induces LTD in the CA1 region. Paired-pulse facilitation of synaptic responses remained unchanged after induction of this LTD, suggesting that it depended on postsynaptic mechanisms. The 8-pCPT-induced LTD was blocked by the Epac signalling inhibitor brefeldin-A (BFA), Rap-1 antagonist geranylgeranyltransferase inhibitor (GGTI) and p38 mitogen activated protein kinase (P38-MAPK) inhibitor SB203580. This indicated a direct involvement of Epac in this form of LTD. As for other forms of LTD, a mimetic peptide of the PSD-95/Disc-large/ZO-1 homology (PDZ) ligand motif of the AMPA receptor subunit GluR2 blocked the Epac-LTD, suggesting involvement of PDZ protein interaction. The Epac-LTD also depended on mobilization of intracellular Ca(2+), proteasome activity and mRNA translation, but not transcription, as it was inhibited by thapsigargin, lactacystin and anisomycin, but not actinomycin-D, respectively. Finally, we found that the pituitary adenylate cyclase activating polypeptide (PACAP) can induce an LTD that was mutually occluded by the Epac-LTD and blocked by BFA or SB203580, suggesting that the Epac-LTD could be mobilized by stimulation of PACAP receptors. Altogether these results provided evidence for a new form of hippocampal LTD.
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PMID:Epac mediates PACAP-dependent long-term depression in the hippocampus. 1956 45

Synaptic scaling has been proposed as a form of plasticity that may contribute to drug addiction but it has not been previously demonstrated in the nucleus accumbens (NAc), a critical region for addiction. Here we demonstrate bidirectional synaptic scaling in postnatal rat NAc neurons that were co-cultured with prefrontal cortical neurons to restore excitatory input. Prolonged activity blockade (1-3 days) with an AMPA receptor antagonist increased cell surface (synaptic and extrasynaptic) glutamate receptor 1 (GluR1) and GluR2 but not GluR3, as well as GluR1/2 co-localization on the cell surface and total GluR1 and GluR2 protein levels. A prolonged increase in activity (bicuculline, 48 h) produced opposite effects. These results suggest that GluR1/2-containing AMPA receptors undergo synaptic scaling in NAc neurons. GluR1 and GluR2 surface expression was also increased by tetrodotoxin alone or in combination with an N-methyl-d-aspartate receptor or AMPA receptor antagonist but not by the l-type Ca(2+) channel antagonist nifedipine. A cobalt-quenching assay confirmed the immunocytochemical results indicating that synaptic scaling after activity blockade did not involve a change in abundance of GluR2-lacking AMPA receptors. Increased AMPA receptor surface expression after activity blockade required protein synthesis and was occluded by inhibition of the ubiquitin-proteasome system. Repeated dopamine (DA) treatment, which leads to upregulation of surface GluR1 and GluR2, occluded activity blockade-induced synaptic scaling. These latter results indicate an interaction between cellular mechanisms involved in synaptic scaling and adaptive mechanisms triggered by repeated DA receptor stimulation, suggesting that synaptic scaling may not function normally after exposure to DA-releasing drugs such as cocaine.
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PMID:Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure. 1967 81


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