Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Using the rat model of early life seizures (ELS), which has exaggerated mGluR mediated long-term depression of synaptic strength (mGluR-LTD) in adulthood, we probed the signaling cascades underlying mGluR-LTD induction. Several inhibitors completely blocked mGluR-LTD in control but not in ELS rats: the proteasome, the mammalian target of rapamycin (mTOR), S6 kinase (S6K), or L-type voltage-gated calcium channels (L-type VGCC). Inhibition of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) resulted in a near complete block of mGluR-LTD in control rats and a slight reduction of mGluR-LTD in ELS rats. "Autonomous" CaMKII was found to be upregulated in ELS rats, while elevated S6K activity, which is stimulated by mTOR, was described previously. Thus, modulation of each of these factors was necessary for mGluR-LTD induction in control rats, but even their combined, permanent activation in the ELS rats was not sufficient to individually support mGluR-LTD induction following ELS. This implies that while these factors may act sequentially in controls to mediate mGluR-LTD, this is no longer the case after ELS. In contrast, activated ERK was found to be significantly down-regulated in ELS rats. Inhibition of MEK/ERK activation in control rats elevated mGluR-LTD to the exaggerated levels seen in ELS rats. Together, these results elucidate both the mechanisms that persistently enhance mGluR-LTD after ELS and the mechanisms underlying normal mGluR-LTD by providing evidence for multiple, convergent pathways that mediate mGluR-LTD induction. With our prior work, this ties these signaling cascades to the ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.
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PMID:Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures. 2478 Mar 80

Dendritic protein homeostasis is crucial for most forms of long-term synaptic plasticity, and its dysregulation is linked to a wide range of brain disorders. Current models of metabotropic glutamate receptor mediated long-term depression (mGluR-LTD) suggest that rapid, local synthesis of key proteins is necessary for the induction and expression of LTD. Here, we find that mGluR-LTD can be induced in the absence of translation if the proteasome is concurrently inhibited. We report that enhanced proteasomal degradation during the expression of mGluR-LTD depletes dendritic proteins and inhibits subsequent inductions of LTD. Moreover, proteasome inhibition can rescue mGluR-LTD in mice null for the RNA binding protein Sam68, which we show here lack mGluR-dependent translation and LTD. Our study provides mechanistic insights for how changes in dendritic protein abundance regulate mGluR-LTD induction. We propose that Sam68-mediated translation helps to counterbalance degradation, ensuring that protein levels briefly remain above a permissive threshold during LTD induction.
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PMID:Coordination between Translation and Degradation Regulates Inducibility of mGluR-LTD. 2575 12

A balance of protein synthesis and degradation is critical for the dynamic regulation and implementation of long-term memory storage. The role of the ubiquitin-proteasome system (UPS) in regulating the plasticity at potentiated synapses is well studied, but its roles in depressed synaptic populations remain elusive. In this study, we probed the possibility of regulating the UPS by inhibiting the proteasome function during the induction of protein synthesis-independent form of hippocampal long-term depression (early-LTD), an important component of synaptic plasticity. Here, we show that protein degradation is involved in early-LTD induction and interfering with this process facilitates early-LTD to late-LTD. We provide evidence here that under the circumstances of proteasome inhibition brain-derived neurotrophic factor is accumulated as plasticity-related protein and it drives the weakly depressed or potentiated synapses to associativity. Thus, UPS inhibition promotes LTD and establishes associativity between weakly depressed or potentiated synapses through the mechanisms of synaptic tagging/capture or cross-capture.
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PMID:Ubiquitin-Proteasome System Inhibition Promotes Long-Term Depression and Synaptic Tagging/Capture. 2592 50

Posttranslational modification and degradation of proteins by the ubiquitin-proteasome system (UPS) is crucial to synaptic transmission. It is well established that 19S proteasome associated deubiquitinases (DUBs) reverse the process of ubiquitination by removing ubiquitin from their substrates. However, their potential contribution to hippocampal synaptic plasticity has not been addressed in detail. Here, we report that inhibition of the 19S proteasome associated DUBs, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14) by b-AP15 results in an accumulation of polyubiquitinated proteins and a reduction of monomeric ubiquitin without overt effects on 26S proteasome activity. b-AP15 led to a suppression of mTOR-p70S6K signaling and an increase in levels of p-p38 MAPK, two pathways essentially involved in establishing various forms of activity-dependent plasticity. Additionally, b-AP15 impaired the induction of late-phase long-term potentiation (L-LTP), induced the transformation of mGluR-mediated protein synthesis-independent long-term depression (early-LTD) to L-LTD and promoted heterosynaptic stabilization through synaptic tagging/capture (STC) in the hippocampal CA1 region of mice. The activity of 19S proteasome associated DUBs was also required for the enhancement of short-term potentiation (STP) induced by brain-derived neurotrophic factor (BDNF). Altogether, these results indicate an essential role of 19S proteasome associated DUBs in regulating activity-dependent hippocampal synaptic plasticity.
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PMID:The role of 19S proteasome associated deubiquitinases in activity-dependent hippocampal synaptic plasticity. 2940 17