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1.
Cell ; 139(4): 814-27, 2009 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-19914173

RESUMO

Acquired memory initially depends on the hippocampus (HPC) for the process of cortical permanent memory formation. The mechanisms through which memory becomes progressively independent from the HPC remain unknown. In the HPC, adult neurogenesis has been described in many mammalian species, even at old ages. Using two mouse models in which hippocampal neurogenesis is physically or genetically suppressed, we show that decreased neurogenesis is accompanied by a prolonged HPC-dependent period of associative fear memory. Inversely, enhanced neurogenesis by voluntary exercise sped up the decay rate of HPC dependency of memory, without loss of memory. Consistently, decreased neurogenesis facilitated the long-lasting maintenance of rat hippocampal long-term potentiation in vivo. These independent lines of evidence strongly suggest that the level of hippocampal neurogenesis play a role in determination of the HPC-dependent period of memory in adult rodents. These observations provide a framework for understanding the mechanisms of the hippocampal-cortical complementary learning systems.


Assuntos
Condicionamento Clássico , Medo/fisiologia , Hipocampo/citologia , Animais , Giro Denteado/fisiologia , Folistatina/farmacologia , Hipocampo/fisiologia , Hipocampo/efeitos da radiação , Potenciação de Longa Duração/efeitos da radiação , Camundongos , Neurogênese/efeitos dos fármacos , Neurogênese/efeitos da radiação , Ratos , Raios X
2.
EMBO Rep ; 20(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30622218

RESUMO

Promoter-associated long non-coding RNAs (lncRNAs) regulate the expression of adjacent genes; however, precise roles of these lncRNAs in skeletal muscle remain largely unknown. Here, we characterize a promoter-associated lncRNA, Myoparr, in myogenic differentiation and muscle disorders. Myoparr is expressed from the promoter region of the mouse and human myogenin gene, one of the key myogenic transcription factors. We show that Myoparr is essential both for the specification of myoblasts by activating neighboring myogenin expression and for myoblast cell cycle withdrawal by activating myogenic microRNA expression. Mechanistically, Myoparr interacts with Ddx17, a transcriptional coactivator of MyoD, and regulates the association between Ddx17 and the histone acetyltransferase PCAF Myoparr also promotes skeletal muscle atrophy caused by denervation, and knockdown of Myoparr rescues muscle wasting in mice. Our findings demonstrate that Myoparr is a novel key regulator of muscle development and suggest that Myoparr is a potential therapeutic target for neurogenic atrophy in humans.


Assuntos
Diferenciação Celular/genética , Desenvolvimento Muscular/genética , Miogenina/genética , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , Animais , Ciclo Celular , Linhagem Celular , RNA Helicases DEAD-box/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/patologia , Proteína MyoD/metabolismo , Mioblastos/citologia , Mioblastos/metabolismo , Ligação Proteica , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
3.
Cell Mol Life Sci ; 76(24): 4829-4848, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31363817

RESUMO

Exosomes, a type of small extracellular vesicles (sEVs), are secreted membrane vesicles that are derived from various cell types, including cancer cells, mesenchymal stem cells, and immune cells via multivesicular bodies (MVBs). These sEVs contain RNAs (mRNA, miRNA, lncRNA, and rRNA), lipids, DNA, proteins, and metabolites, all of which mediate cell-to-cell communication. This communication is known to be implicated in a diverse set of diseases such as cancers and their metastases and degenerative diseases. The molecular mechanisms, by which proteins are modified and sorted to sEVs, are not fully understood. Various cellular processes, including degradation, transcription, DNA repair, cell cycle, signal transduction, and autophagy, are known to be associated with ubiquitin and ubiquitin-like proteins (UBLs). Recent studies have revealed that ubiquitin and UBLs also regulate MVBs and protein sorting to sEVs. Ubiquitin-like 3 (UBL3)/membrane-anchored Ub-fold protein (MUB) acts as a post-translational modification (PTM) factor to regulate efficient protein sorting to sEVs. In this review, we focus on the mechanism of PTM by ubiquitin and UBLs and the pathway of protein sorting into sEVs and discuss the potential biological significance of these processes.


Assuntos
Processamento de Proteína Pós-Traducional/genética , Proteínas/genética , Ubiquitina/genética , Ubiquitinas/genética , Autofagia/genética , Exossomos/genética , Vesículas Extracelulares/genética , Humanos , Células-Tronco Mesenquimais/metabolismo , Corpos Multivesiculares/genética , Corpos Multivesiculares/metabolismo , Proteínas/metabolismo , Transdução de Sinais
4.
Mol Brain ; 17(1): 57, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39148092

RESUMO

Discovery of novel post-translational modifications provides new insights into changes in protein function, localization, and stability. They are also key elements in understanding disease mechanisms and developing therapeutic strategies. We have previously reported that ubiquitin-like 3 (UBL3) serves as a novel post-translational modifier that is highly expressed in the cerebral cortex and hippocampus, in addition to various other organs, and that 60% of proteins contained in small extracellular vesicles (sEVs), including exosomes, are influenced by UBL3. In this study, we generated transgenic mice expressing biotinylated UBL3 in the forebrain under control of the alpha-CaMKII promoter (Ubl3Tg/+). Western blot analysis revealed that the expression of UBL3 in the cerebral cortex and hippocampus was 6- to 7-fold higher than that in the cerebellum. Therefore, we performed immunoprecipitation of protein extracts from the cerebral cortex of Ubl3+/+ and Ubl3Tg/+ mice using avidin beads to comprehensively discover UBL3 interacting proteins, identifying 35 new UBL3 interacting proteins. Nine proteins were annotated as extracellular exosomes. Gene Ontology (GO) analysis suggested a new relationship between sEVs and RNA metabolism in neurodegenerative diseases. We confirmed the association of endogenous UBL3 with the RNA-binding proteins FUS and HPRT1-both listed in the Neurodegenerative Diseases Variation Database (NDDVD)-and with LYPLA1, which is involved in Huntington's disease, using immunoprecipitation (IP)-western blotting analysis. These UBL3 interacting proteins will accelerate the continued elucidation of sEV research about proteins regulated by novel post-translational modifications by UBL3 in the brain.


Assuntos
Encéfalo , Ubiquitinas , Animais , Camundongos , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Exossomos/metabolismo , Ontologia Genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ligação Proteica , Ubiquitinas/metabolismo
5.
Biomarkers ; 18(7): 565-72, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23937207

RESUMO

OBJECTIVE: We performed comprehensive proteomic analyses of articular cartilage by using the isobaric tags for relative and absolute quantitation (iTRAQ) method, and searched for candidate biomarkers for osteoarthritis (OA). METHODS: Articular cartilage was collected from patients with OA or femoral neck fracture for the control group. Molecular variations were detected by the iTRAQ method, and quantitative analyses were performed by western blot. RESULTS: Using the iTRAQ method, we identified 76 proteins with different expression levels in OA patients and the control group. Among these proteins, we selected LECT2 (leukocyte cell-derived chemotaxin-2), BAALC (brain and acute leukemia, cytoplasmic), and PRDX6 (peroxiredoxin-6), which had not been reported as biomarkers for OA. CONCLUSIONS: Use of these proteins in combination with conventional OA biomarkers may better reflect the grade and prognosis of OA.


Assuntos
Cartilagem Articular/metabolismo , Cabeça do Fêmur/metabolismo , Osteoartrite do Quadril/metabolismo , Osteoartrite do Joelho/metabolismo , Proteoma/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Osteoartrite do Quadril/diagnóstico , Osteoartrite do Joelho/diagnóstico , Peroxirredoxina VI/metabolismo , Prognóstico , Proteômica
6.
Learn Mem ; 17(4): 176-85, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20332189

RESUMO

A recent study has revealed that fear memory may be vulnerable following retrieval, and is then reconsolidated in a protein synthesis-dependent manner. However, little is known about the molecular mechanisms of these processes. Activin betaA, a member of the TGF-beta superfamily, is increased in activated neuronal circuits and regulates dendritic spine morphology. To clarify the role of activin in the synaptic plasticity of the adult brain, we examined the effect of inhibiting or enhancing activin function on hippocampal long-term potentiation (LTP). We found that follistatin, a specific inhibitor of activin, blocked the maintenance of late LTP (L-LTP) in the hippocampus. In contrast, administration of activin facilitated the maintenance of early LTP (E-LTP). We generated forebrain-specific activin- or follistatin-transgenic mice in which transgene expression is under the control of the Tet-OFF system. Maintenance of hippocampal L-LTP was blocked in the follistatin-transgenic mice. In the contextual fear-conditioning test, we found that follistatin blocked the formation of long-term memory (LTM) without affecting short-term memory (STM). Furthermore, consolidated memory was selectively weakened by the expression of follistatin during retrieval, but not during the maintenance phase. On the other hand, the maintenance of memory was also influenced by activin overexpression during the retrieval phase. Thus, the level of activin in the brain during the retrieval phase plays a key role in the maintenance of long-term memory.


Assuntos
Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Animais , Comportamento Animal , Biofísica , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiologia , Doxiciclina/administração & dosagem , Estimulação Elétrica/métodos , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Medo , Folistatina/genética , Folistatina/farmacologia , Lateralidade Funcional , Técnicas In Vitro , Subunidades beta de Inibinas/genética , Subunidades beta de Inibinas/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Prosencéfalo/metabolismo , Ratos , Ratos Wistar
7.
Cell Commun Signal ; 7: 15, 2009 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-19538713

RESUMO

After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-beta (TGF-beta) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-beta, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-beta ligands, and control the signaling and availability of ligands.The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of this pathway as a molecular target of therapy for metabolic diseases, musculoskeletal disorders, cancers and neural damages.

8.
Nat Commun ; 9(1): 3936, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258067

RESUMO

Exosomes, a type of small extracellular vesicles (sEVs), derived from multivesicular bodies (MVBs), mediate cell-to-cell communication by transporting proteins, mRNAs, and miRNAs. However, the molecular mechanism by which proteins are sorted to sEVs is not fully understood. Here, we report that ubiquitin-like 3 (UBL3)/membrane-anchored Ub-fold protein (MUB) acts as a posttranslational modification (PTM) factor that regulates protein sorting to sEVs. We find that UBL3 modification is indispensable for sorting of UBL3 to MVBs and sEVs. We also observe a 60% reduction of total protein levels in sEVs purified from Ubl3-knockout mice compared with those from wild-type mice. By performing proteomics analysis, we find 1241 UBL3-interacting proteins, including Ras. We also show that UBL3 directly modifies Ras and oncogenic RasG12V mutant, and that UBL3 expression enhances sorting of RasG12V to sEVs via UBL3 modification. Collectively, these results indicate that PTM by UBL3 influences the sorting of proteins to sEVs.


Assuntos
Vesículas Extracelulares/metabolismo , Processamento de Proteína Pós-Traducional , Ubiquitinas/metabolismo , Animais , Células HEK293 , Células HeLa , Humanos , Camundongos Knockout , Transporte Proteico , Ubiquitinas/genética
9.
Vitam Horm ; 85: 185-206, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21353881

RESUMO

Activins, which are members of the TGF-ß superfamily, were initially isolated from gonads and served as modulators of follicle-stimulating hormone secretion. Activins regulate various biological functions, including induction of the dorsal mesoderm, craniofacial development, and differentiation of numerous cell types. Activin receptors are highly expressed in neuronal cells, and activin mRNA expression is upregulated by neuronal activity. Activins also exhibit neuroprotective action during excitotoxic brain injury. However, very little is known about the functional roles of activins in the brain. We recently generated various types of transgenic mice, demonstrating that activins regulate spine formation, behavioral activity, anxiety, adult neurogenesis, late-phase long-term potentiation, and maintenance of long-term memory. The present chapter describes recent progress in the study of the role of activin in the brain.


Assuntos
Ativinas/fisiologia , Encéfalo/metabolismo , Neurônios/metabolismo , Animais , Ansiedade/metabolismo , Humanos , Memória , Neurogênese
10.
Med Mol Morphol ; 42(1): 16-23, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19294488

RESUMO

Lipids are major structural component of the brain and play key roles in signaling functions in the central nervous system (CNS), such as the hippocampus. In particular, sulfatide is an abundant glycosphingolipid component of both the central and the peripheral nervous system and is an essential lipid component of myelin membranes. Lack of sulfatide is observed in myelin deformation and neurological deficits. Previous studies with antisulfatide antibody have investigated distribution of sulfatide expression in neurons; however, this method cannot distinguish the differences of sulfatide lipid species raised by difference of carbon-chain length in the ceramide portion in addition to the differences of sulfatide and seminolipid. In this study, we solved the problem by our recently developed nanoparticle-assisted laser desorption/ionization (nano-PALDI)-based imaging mass spectrometry (IMS). We revealed that the level of sulfatide in the middle molecular layer was significantly higher than that in granule cell layers and the inner molecular layer in the dentate gyrus of rat hippocampus.


Assuntos
Hipocampo/metabolismo , Sulfoglicoesfingolipídeos/metabolismo , Animais , Giro Denteado/anatomia & histologia , Giro Denteado/metabolismo , Hipocampo/anatomia & histologia , Imuno-Histoquímica , Estrutura Molecular , Nanopartículas , Ratos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Sulfoglicoesfingolipídeos/química , Espectrometria de Massas em Tandem , Distribuição Tecidual
11.
PLoS One ; 3(4): e1869, 2008 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-18382659

RESUMO

Activin, a member of the transforming growth factor-beta superfamily, is an endocrine hormone that regulates differentiation and proliferation of a wide variety of cells. In the brain, activin protects neurons from ischemic damage. In this study, we demonstrate that activin modulates anxiety-related behavior by analyzing ACM4 and FSM transgenic mice in which activin and follistatin (which antagonizes the activin signal), respectively, were overexpressed in a forebrain-specific manner under the control of the alphaCaMKII promoter. Behavioral analyses revealed that FSM mice exhibited enhanced anxiety compared to wild-type littermates, while ACM4 mice showed reduced anxiety. Importantly, survival of newly formed neurons in the subgranular zone of adult hippocampus was significantly decreased in FSM mice, which was partially rescued in ACM4/FSM double transgenic mice. Our findings demonstrate that the level of activin in the adult brain bi-directionally influences anxiety-related behavior. These results further suggest that decreases in postnatal neurogenesis caused by activin inhibition affect an anxiety-related behavior in adulthood. Activin and its signaling pathway may represent novel therapeutic targets for anxiety disorder as well as ischemic brain injury.


Assuntos
Ativinas/genética , Ativinas/fisiologia , Encéfalo/metabolismo , Folistatina/genética , Neurônios/metabolismo , Ativinas/química , Ativinas/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Diferenciação Celular , Folistatina/metabolismo , Hipocampo/metabolismo , Isquemia/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Fenótipo , Regiões Promotoras Genéticas , Transgenes
12.
PLoS One ; 3(7): e2809, 2008 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-18665261

RESUMO

Some ubiquitin-like (UBL) domain-containing proteins are known to play roles in receptor trafficking. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) undergo constitutive cycling between the intracellular compartment and the cell surface in the central nervous system. However, the function of UBL domain-containing proteins in the recycling of the AMPARs to the synaptic surface has not yet been reported.Here, we report that the Transmembrane and ubiquitin-like domain-containing 1 (Tmub1) protein, formerly known as the Hepatocyte Odd Protein Shuttling (HOPS) protein, which is abundantly expressed in the brain and which exists in a synaptosomal membrane fraction, facilitates the recycling of the AMPAR subunit GluR2 to the cell surface. Neurons transfected with Tmub1/HOPS-RNAi plasmids showed a significant reduction in the AMPAR current as compared to their control neurons. Consistently, the synaptic surface expression of GluR2, but not of GluR1, was significantly decreased in the neurons transfected with the Tmub1/HOPS-RNAi and increased in the neurons overexpressing EGFP-Tmub1/HOPS. The altered surface expression of GluR2 was speculated to be due to the altered surface-recycling of the internalized GluR2 in our recycling assay. Eventually, we found that GluR2 and glutamate receptor interacting protein (GRIP) were coimmunoprecipitated by the anti-Tmub1/HOPS antibody from the mouse brain. Taken together, these observations show that the Tmub1/HOPS plays a role in regulating basal synaptic transmission; it contributes to maintain the synaptic surface number of the GluR2-containing AMPARs by facilitating the recycling of GluR2 to the plasma membrane.


Assuntos
Proteínas de Transporte/fisiologia , Proteínas Nucleares/fisiologia , Receptores de AMPA/fisiologia , Ubiquitina/química , Animais , Encéfalo/metabolismo , Proteínas de Transporte/biossíntese , Membrana Celular/metabolismo , Biologia Computacional/métodos , Endossomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Proteínas Nucleares/biossíntese , Plasmídeos/metabolismo , Estrutura Terciária de Proteína , Interferência de RNA , Receptores de AMPA/metabolismo , Sinaptossomos/metabolismo
13.
J Cell Sci ; 120(Pt 21): 3830-7, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17940062

RESUMO

Long-lasting modifications in synaptic transmission depend on de novo gene expression in neurons. The expression of activin, a member of the transforming growth factor beta (TGF-beta) superfamily, is upregulated during hippocampal long-term potentiation (LTP). Here, we show that activin increased the average number of presynaptic contacts on dendritic spines by increasing the population of spines that were contacted by multiple presynaptic terminals in cultured neurons. Activin also induced spine lengthening, primarily by elongating the neck, resulting in longer mushroom-shaped spines. The number of spines and spine head size were not significantly affected by activin treatment. The effects of activin on spinal filamentous actin (F-actin) morphology were independent of protein and RNA synthesis. Inhibition of cytoskeletal actin dynamics or of the mitogen-activated protein (MAP) kinase pathway blocked not only the activin-induced increase in the number of terminals contacting a spine but also the activin-induced lengthening of spines. These results strongly suggest that activin increases the number of synaptic contacts by modulating actin dynamics in spines, a process that might contribute to the establishment of late-phase LTP.


Assuntos
Actinas/metabolismo , Ativinas/metabolismo , Dendritos , Sinapses/metabolismo , Actinas/ultraestrutura , Ativinas/genética , Animais , Células Cultivadas , Dendritos/metabolismo , Dendritos/ultraestrutura , Hipocampo/citologia , Potenciação de Longa Duração/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Ratos , Sinapses/ultraestrutura , Transmissão Sináptica/fisiologia
14.
Cell ; 130(5): 943-57, 2007 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-17803915

RESUMO

Little is known about how synaptic activity is modulated in the central nervous system. We have identified SCRAPPER, a synapse-localized E3 ubiquitin ligase, which regulates neural transmission. SCRAPPER directly binds and ubiquitinates RIM1, a modulator of presynaptic plasticity. In neurons from Scrapper-knockout (SCR-KO) mice, RIM1 had a longer half-life with significant reduction in ubiquitination, indicating that SCRAPPER is the predominant ubiquitin ligase that mediates RIM1 degradation. As anticipated in a RIM1 degradation defect mutant, SCR-KO mice displayed altered electrophysiological synaptic activity, i.e., increased frequency of miniature excitatory postsynaptic currents. This phenotype of SCR-KO mice was phenocopied by RIM1 overexpression and could be rescued by re-expression of SCRAPPER or knockdown of RIM1. The acute effects of proteasome inhibitors, such as upregulation of RIM1 and the release probability, were blocked by the impairment of SCRAPPER. Thus, SCRAPPER has an essential function in regulating proteasome-mediated degradation of RIM1 required for synaptic tuning.


Assuntos
Encéfalo/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Processamento de Proteína Pós-Traducional , Sinapses/metabolismo , Transmissão Sináptica , Vesículas Sinápticas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Potenciais Pós-Sinápticos Excitadores , Proteínas F-Box , Proteínas de Ligação ao GTP/deficiência , Proteínas de Ligação ao GTP/genética , Genótipo , Meia-Vida , Cinética , Leupeptinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso , Plasticidade Neuronal , Neurônios/enzimologia , Neurônios/metabolismo , Fenótipo , Terminações Pré-Sinápticas/enzimologia , Terminações Pré-Sinápticas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos , Sinapses/enzimologia , Transmissão Sináptica/efeitos dos fármacos , Vesículas Sinápticas/efeitos dos fármacos , Transfecção , Complexos Ubiquitina-Proteína Ligase , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética
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