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

---

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

Chronic increases or decreases in neuronal activity initiates compensatory changes in synaptic strength that emerge slowly over a 12-24 h period, but the mechanisms underlying this slow homeostatic response remain poorly understood. Here, we show an essential role for the ubiquitin proteasome system (UPS) in slow homeostatic plasticity induced by chronic changes in network activity. In cultured hippocampal neurons, UPS inhibitors drive a slow increase in miniature excitatory postsynaptic current (mEPSC) amplitude and synaptic AMPA receptor subunit GluA1 and GluA2 expression that both mirrors and occludes the changes produced by chronic suppression of network activity with tetrodotoxin (TTX). These non-additive effects were similarly observed under conditions of chronic hyperactivation of network activity with bicuculline--the increase in mEPSC amplitude and GluA1/2 expression with chronic UPS inhibition persists during network hyperactivation, which scales synaptic strength and AMPA receptor expression in the opposite direction when UPS activity is intact. Finally, cell-autonomous UPS inhibition (via expression of the ubiquitin chain elongation mutant, UbK48R) enhances mEPSC amplitude in a manner that mimics and occludes changes in network activity, demonstrating a postsynaptic role for the UPS in slow homeostatic plasticity. Taken together, our results suggest that the UPS acts as an integration point for translating sustained changes in network activity into appropriate incremental compensatory changes at synapses.
...
PMID:An essential postsynaptic role for the ubiquitin proteasome system in slow homeostatic synaptic plasticity in cultured hippocampal neurons. 2088 92

Ras and Rap small GTPases are important for synaptic plasticity and memory. However, their roles in homeostatic plasticity are unknown. Here, we report that polo-like kinase 2 (Plk2), a homeostatic suppressor of overexcitation, governs the activity of Ras and Rap via coordination of their regulatory proteins. Plk2 directs elimination of Ras activator RasGRF1 and Rap inhibitor SPAR via phosphorylation-dependent ubiquitin-proteasome degradation. Conversely, Plk2 phosphorylation stimulates Ras inhibitor SynGAP and Rap activator PDZGEF1. These Ras/Rap regulators perform complementary functions to downregulate dendritic spines and AMPA receptors following elevated activity, and their collective regulation by Plk2 profoundly stimulates Rap and suppresses Ras. Furthermore, perturbation of Plk2 disrupts Ras and Rap signaling, prevents homeostatic shrinkage and loss of dendritic spines, and impairs proper memory formation. Our study demonstrates a critical role of Plk2 in the synchronized tuning of Ras and Rap and underscores the functional importance of this regulation in homeostatic synaptic plasticity.
...
PMID:Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory. 2138 55

At synapses, two major processes occur concomitantly after the release of glutamate: activation of AMPA receptors (AMPARs) to conduct synaptic transmission and activation of excitatory amino acid transporters (EAATs) for transmitter removal. Although crosstalk between the receptors and EAATs is conceivable, whether and how the transporter activity affects AMPAR synaptic localization remain unknown. Using cultured hippocampal and cortical rat neurons, we show that inhibition of glutamate transporters leads to rapid reduction in AMPAR synaptic accumulation and total AMPAR abundance. EAAT inactivity also results in elevated internalization and reduced surface expression of AMPARs. The reduction in AMPAR amount is accompanied by receptor ubiquitination and can be blocked by suppression of proteasome activity, indicating the involvement of proteasome-mediated receptor degradation. Consistent with glutamate spillover, effect of EAAT inhibition on AMPAR distribution and stability is dependent on the activation of parasynaptically localized NR2B-containing NMDA receptors (NMDARs). Moreover, we show that neuronal glutamate transporters, especially those localized at the postsynaptic sites, are responsible for the observed effect during EAAT suppression. These results indicate a role for neuron-specific glutamate transporters in AMPAR synaptic localization and stability.
...
PMID:Parasynaptic NMDA receptor signaling couples neuronal glutamate transporter function to AMPA receptor synaptic distribution and stability. 2239 28

NMDA receptors play a central role in shaping the strength of synaptic connections throughout development and in mediating synaptic plasticity mechanisms that underlie some forms of learning and memory formation in the CNS. In the hippocampus and the neocortex, GluN1 is combined primarily with GluN2A and GluN2B, which are differentially expressed during development and confer distinct molecular and physiological properties to NMDA receptors. The contribution of each subunit to the synaptic traffic of NMDA receptors and therefore to their role during development and in synaptic plasticity is still controversial. We report a critical role for the GluN2B subunit in regulating NMDA receptor synaptic targeting. In the absence of GluN2B, the synaptic levels of AMPA receptors are increased and accompanied by decreased constitutive endocytosis of GluA1-AMPA receptor. We used quantitative proteomic analysis to identify changes in the composition of postsynaptic densities from GluN2B(-/-) mouse primary neuronal cultures and found altered levels of several ubiquitin proteasome system components, in particular decreased levels of proteasome subunits. Enhancing the proteasome activity with a novel proteasome activator restored the synaptic levels of AMPA receptors in GluN2B(-/-) neurons and their endocytosis, revealing that GluN2B-mediated anchoring of the synaptic proteasome is responsible for fine tuning AMPA receptor synaptic levels under basal conditions.
...
PMID:GluN2B-Containing NMDA Receptors Regulate AMPA Receptor Traffic through Anchoring of the Synaptic Proteasome. 2604 15

Long-term potentiation (LTP) and long-term depression (LTD) are crucial for synaptic plasticity, and are driven by AMPA receptor (AMPAR) trafficking. Recent findings indicate that the ubiquitin-proteasome system, the main protein degradation machinery of the cell, plays a significant role in memory formation by regulating the induction and maintenance of LTP. Although previously suggested as a possibility, deubiquitination of mammalian AMPARs had not been demonstrated, and the search for an enzyme that mediates the processes continued. This Editorial Highlight discusses the relevance of a study published in the current issue of Journal of Neurochemistry, in which the authors Huo and collaborators now identified ubiquitin-specific peptidase 46 (USP46) as a specific AMPAR deubiquitinase.
...
PMID:USP46: a new piece of the memory puzzle? 2607 8

Estrogen is an important modulator of hippocampal synaptic plasticity and memory consolidation through its rapid action on membrane-associated receptors. Here, we found that both estradiol and the G-protein-coupled estrogen receptor 1 (GPER1) specific agonist G1 rapidly induce brain-derived neurotrophic factor (BDNF) release, leading to transient stimulation of activity-regulated cytoskeleton-associated (Arc) protein translation and GluA1-containing AMPA receptor internalization in field CA3 of hippocampus. We also show that type-I metabotropic glutamate receptor (mGluR) activation does not induce Arc translation nor long-term depression (LTD) at the mossy fiber pathway, as opposed to its effects in CA1, and it only triggers LTD after GPER1 stimulation. Furthermore, this form of mGluR-dependent LTD is associated with ubiquitination and proteasome-mediated degradation of GluA1, and is prevented by proteasome inhibition. Overall, our study identifies a novel mechanism by which estrogen and BDNF regulate hippocampal synaptic plasticity in the adult brain.
...
PMID:A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release. 2639 61

The long isoform of Fas apoptosis inhibitory molecule (FAIM-L) is a neuron-specific death receptor antagonist that modulates apoptotic cell death and mechanisms of neuronal plasticity. FAIM-L exerts its antiapoptotic action by binding to X-linked inhibitor of apoptosis protein (XIAP), an inhibitor of caspases, which are the main effectors of apoptosis. XIAP levels are regulated by the ubiquitin-proteasome pathway. FAIM-L interaction with XIAP prevents the ubiquitination and degradation of the latter, thereby allowing it to inhibit caspase activation. This interaction also modulates non-apoptotic functions of caspases, such as the endocytosis of AMPA receptor (AMPAR) in hippocampal long-term depression (LTD). The molecular mechanism of action exerted by FAIM-L is unclear since the consensus binding motifs are still unknown. Here, we performed a two-hybrid screening to discover novel FAIM-L-interacting proteins. We found a functional interaction of SIVA-1 with FAIM-L. SIVA-1 is a proapoptotic protein that has the capacity to interact with XIAP. We describe how SIVA-1 regulates FAIM-L function by disrupting the interaction of FAIM-L with XIAP, thereby promoting XIAP ubiquitination, caspase-3 activation and neuronal death. Furthermore, we report that SIVA-1 plays a role in receptor internalization in synapses. SIVA-1 is upregulated upon chemical LTD induction, and it modulates AMPAR internalization via non-apoptotic activation of caspases. In summary, our findings uncover SIVA-1 as new functional partner of FAIM-L and demonstrate its role as a regulator of caspase activity in synaptic function.
...
PMID:SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L. 3201 47

The number and function of synaptic AMPA receptors (AMPARs) tightly regulates excitatory synaptic transmission. Current evidence suggests that AMPARs are inserted into the postsynaptic membrane during long-term potentiation (LTP) and are removed from the membrane during long-term depression (LTD). Dephosphorylation of GluA1 at Ser-845 and enhanced endocytosis are critical events in the modulation of LTD. Moreover, changes in scaffold proteins from the postsynaptic density (PSD) could be also related to AMPAR regulation in LTD. In the present study we analyzed the effect of chemical LTD (cLTD) on A-kinase anchoring protein (AKAP)150 and AMPARs levels in mouse-cultured neurons. We show that cLTD induces AKAP150 protein degradation via proteasome, coinciding with GluA1 dephosphorylation at Ser-845 and endocytosis of GluA1-containing AMPARs. Pharmacological inhibition of proteasome activity, but not phosphatase calcineurin (CaN), reverted cLTD-induced AKAP150 protein degradation. Importantly, AKAP150 silencing induced dephosphorylation of GluA1 Ser-845 and GluA1-AMPARs endocytosis while AKAP150 overexpression blocked cLTD-mediated GluA1-AMPARs endocytosis. Our results provide direct evidence that cLTD-induced AKAP150 degradation by the proteasome contributes to synaptic AMPARs endocytosis.
...
PMID:Proteasomal-Mediated Degradation of AKAP150 Accompanies AMPAR Endocytosis during cLTD. 3220 79


<< Previous 1 2

---