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Pesquisa : D08.811.277.040.330.200 [Categoria DeCS]
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  1 / 2016 MEDLINE  
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[PMID]:29395086
[Au] Autor:Deng S; Ai Y; Gong H; Feng Q; Li X; Chen C; Liu Z; Wang Y; Peng Q; Zhang L
[Ad] Endereço:Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, PR China. Electronic address: dengsy2014@foxmail.com.
[Ti] Título:Mitochondrial dynamics and protective effects of a mitochondrial division inhibitor, Mdivi-1, in lipopolysaccharide-induced brain damage.
[So] Source:Biochem Biophys Res Commun;496(3):865-871, 2018 02 12.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sepsis is one of the most common reasons for mortality in Intensive Care Units. As a common but severe neurological complication, sepsis associated encephalopathy (SAE) has always been ignored and there is no generally accepted treatment. In this study, we demonstrated that Mdivi-1 ameliorated brain damage assessed by Nissl staining. Furthermore, Mdivi-1 reduced TUNEL-positive cells in hippocampus, and inhibited S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) release into plasma. Biochemical analysis also showed that Mdivi-1 protected hippocampus from oxidative stresses. Western blot analysis revealed that Mdivi-1, as a Drp1 inhibitor, inhibited LPS induced dynamin-related GTPase (Drp1) increase. Interestingly, it can also attenuate LPS induced optic atrophy 1 (OPA1) and phosphorylated Drp1 (p-Drp1) decrease. Thus Mdivi-1 protected rats from SAE, and this protective effect could be associated with its inhibition of Drp1 and its activation of p-Drp1 and OPA1. Mitochondrial dynamics may be a potential pharmacological therapeutic target for treating SAE.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Encéfalo/patologia
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Quinazolinonas/administração & dosagem
Encefalopatia Associada a Sepse/tratamento farmacológico
Encefalopatia Associada a Sepse/patologia
[Mh] Termos MeSH secundário: Animais
Encéfalo/efeitos dos fármacos
Relação Dose-Resposta a Droga
Dinaminas/metabolismo
Lipopolissacarídeos
Masculino
Mitocôndrias/patologia
Fármacos Neuroprotetores/administração & dosagem
Ratos
Ratos Sprague-Dawley
Encefalopatia Associada a Sepse/metabolismo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone); 0 (Lipopolysaccharides); 0 (Neuroprotective Agents); 0 (Quinazolinones); EC 3.6.5.5 (Drp1 protein, rat); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180204
[St] Status:MEDLINE


  2 / 2016 MEDLINE  
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[PMID]:29223396
[Au] Autor:Matsuishi YI; Kato H; Masuda K; Yamaza H; Hirofuji Y; Sato H; Wada H; Kiyoshima T; Nonaka K
[Ad] Endereço:Section of Oral Medicine for Children, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
[Ti] Título:Accelerated dentinogenesis by inhibiting the mitochondrial fission factor, dynamin related protein 1.
[So] Source:Biochem Biophys Res Commun;495(2):1655-1660, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Undifferentiated odontogenic epithelium and dental papilla cells differentiate into ameloblasts and odontoblasts, respectively, both of which are essential for tooth development. These differentiation processes involve dramatic functional and morphological changes of the cells. For these changes to occur, activation of mitochondrial functions, including ATP production, is extremely important. In addition, these changes are closely related to mitochondrial fission and fusion, known as mitochondrial dynamics. However, few studies have focused on the role of mitochondrial dynamics in tooth development. The purpose of this study was to clarify this role. We used mouse tooth germ organ cultures and a mouse dental papilla cell line with the ability to differentiate into odontoblasts, in combination with knockdown of the mitochondrial fission factor, dynamin related protein (DRP)1. In organ cultures of the mouse first molar, tooth germ developed to the early bell stage. The amount of dentin formed under DRP1 inhibition was significantly larger than that of the control. In experiments using a mouse dental papilla cell line, differentiation into odontoblasts was enhanced by inhibiting DRP1. This was associated with increased mitochondrial elongation and ATP production compared to the control. These results suggest that DRP1 inhibition accelerates dentin formation through mitochondrial elongation and activation. This raises the possibility that DRP1 might be a therapeutic target for developmental disorders of teeth.
[Mh] Termos MeSH primário: Dentinogênese/fisiologia
Dinaminas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/biossíntese
Ameloblastos/citologia
Ameloblastos/fisiologia
Animais
Diferenciação Celular/genética
Diferenciação Celular/fisiologia
Linhagem Celular
Dinaminas/genética
Dinaminas/fisiologia
Proteínas da Matriz Extracelular/biossíntese
Feminino
Camundongos
Camundongos Endogâmicos C57BL
Dinâmica Mitocondrial/fisiologia
Odontoblastos/citologia
Odontoblastos/fisiologia
Técnicas de Cultura de Órgãos
Fosfoproteínas/biossíntese
Gravidez
RNA Interferente Pequeno/genética
Sialoglicoproteínas/biossíntese
Germe de Dente/citologia
Germe de Dente/embriologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Extracellular Matrix Proteins); 0 (Phosphoproteins); 0 (RNA, Small Interfering); 0 (Sialoglycoproteins); 0 (dentin sialophosphoprotein); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.5.5 (Dnm1l protein, mouse); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171211
[St] Status:MEDLINE


  3 / 2016 MEDLINE  
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[PMID]:29217195
[Au] Autor:Bo T; Yamamori T; Suzuki M; Sakai Y; Yamamoto K; Inanami O
[Ad] Endereço:Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
[Ti] Título:Calmodulin-dependent protein kinase II (CaMKII) mediates radiation-induced mitochondrial fission by regulating the phosphorylation of dynamin-related protein 1 (Drp1) at serine 616.
[So] Source:Biochem Biophys Res Commun;495(2):1601-1607, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitochondrial dynamics are suggested to be indispensable for the maintenance of cellular quality and function in response to various stresses. While ionizing radiation (IR) stimulates mitochondrial fission, which is mediated by the mitochondrial fission protein, dynamin-related protein 1 (Drp1), it remains unclear how IR promotes Drp1 activation and subsequent mitochondrial fission. Therefore, we conducted this study to investigate these concerns. First, we found that X-irradiation triggered Drp1 phosphorylation at serine 616 (S616) but not at serine 637 (S637). Reconstitution analysis revealed that introduction of wild-type (WT) Drp1 recovered radiation-induced mitochondrial fission, which was absent in Drp1-deficient cells. Compared with cells transfected with WT or S637A Drp1, the change in mitochondrial shape following irradiation was mitigated in S616A Drp1-transfected cells. Furthermore, inhibition of CaMKII significantly suppressed Drp1 S616 phosphorylation and mitochondrial fission induced by IR. These results suggest that Drp1 phosphorylation at S616, but not at S637, is prerequisite for radiation-induced mitochondrial fission and that CaMKII regulates Drp1 phosphorylation at S616 following irradiation.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo
Dinaminas/metabolismo
Dinâmica Mitocondrial/fisiologia
Dinâmica Mitocondrial/efeitos da radiação
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Benzilaminas/farmacologia
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Células Cultivadas
Dinaminas/química
Dinaminas/genética
Camundongos
Mitocôndrias/metabolismo
Mitocôndrias/efeitos da radiação
Dinâmica Mitocondrial/efeitos dos fármacos
Mutagênese Sítio-Dirigida
Fosforilação/efeitos dos fármacos
Fosforilação/efeitos da radiação
Inibidores de Proteínas Quinases/farmacologia
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Serina/química
Sulfonamidas/farmacologia
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzylamines); 0 (KN 92); 0 (Protein Kinase Inhibitors); 0 (Recombinant Proteins); 0 (Sulfonamides); 139298-40-1 (KN 93); 452VLY9402 (Serine); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2); EC 3.6.5.5 (Dnm1l protein, mouse); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


  4 / 2016 MEDLINE  
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[PMID]:28463107
[Au] Autor:Monterisi S; Lobo MJ; Livie C; Castle JC; Weinberger M; Baillie G; Surdo NC; Musheshe N; Stangherlin A; Gottlieb E; Maizels R; Bortolozzi M; Micaroni M; Zaccolo M
[Ad] Endereço:Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
[Ti] Título:PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling.
[So] Source:Elife;6, 2017 05 02.
[Is] ISSN:2050-084X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:cAMP/PKA signalling is compartmentalised with tight spatial and temporal control of signal propagation underpinning specificity of response. The cAMP-degrading enzymes, phosphodiesterases (PDEs), localise to specific subcellular domains within which they control local cAMP levels and are key regulators of signal compartmentalisation. Several components of the cAMP/PKA cascade are located to different mitochondrial sub-compartments, suggesting the presence of multiple cAMP/PKA signalling domains within the organelle. The function and regulation of these domains remain largely unknown. Here, we describe a novel cAMP/PKA signalling domain localised at mitochondrial membranes and regulated by PDE2A2. Using pharmacological and genetic approaches combined with real-time FRET imaging and high resolution microscopy, we demonstrate that in rat cardiac myocytes and other cell types mitochondrial PDE2A2 regulates local cAMP levels and PKA-dependent phosphorylation of Drp1. We further demonstrate that inhibition of PDE2A, by enhancing the hormone-dependent cAMP response locally, affects mitochondria dynamics and protects from apoptotic cell death.
[Mh] Termos MeSH primário: Apoptose
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
AMP Cíclico/metabolismo
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo
Dinaminas/metabolismo
Mitocôndrias/metabolismo
Mitocôndrias/ultraestrutura
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Seres Humanos
Camundongos
Fosforilação
Processamento de Proteína Pós-Traducional
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 2); EC 3.1.4.17 (Pde2a protein, rat); EC 3.6.5.5 (Drp1 protein, rat); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180211
[Lr] Data última revisão:
180211
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  5 / 2016 MEDLINE  
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[PMID]:28968439
[Au] Autor:Kim JH; Park SJ; Kim B; Choe YG; Lee DS
[Ad] Endereço:School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
[Ti] Título:Insulin-stimulated lipid accumulation is inhibited by ROS-scavenging chemicals, but not by the Drp1 inhibitor Mdivi-1.
[So] Source:PLoS One;12(10):e0185764, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adipocyte differentiation is regulated by intracellular reactive oxygen species (ROS) generation and mitochondrial fission and fusion processes. However, the correlation between intracellular ROS generation and mitochondrial remodeling during adipocyte differentiation is still unknown. Here, we investigated the effect on adipocyte differentiation of 3T3-L1 cells of intracellular ROS inhibition using N-acetyl cysteine (Nac) and Mito-TEMPO and of mitochondrial fission inhibition using Mdivi-1. Differentiated 3T3-L1 adipocytes displayed an increase in mitochondrial fission, ROS generation, and the expression of adipogenic and mitochondrial dynamics-related proteins. ROS scavenger (Nac or Mito-TEMPO) treatment inhibited ROS production, lipid accumulation, the expression of adipogenic and mitochondrial dynamics-related proteins, and mitochondrial fission during adipogenesis of 3T3-L1 cells. On the other hand, treatment with the mitochondrial fission inhibitor Mdivi-1 inhibited mitochondrial fission but did not inhibit ROS production, lipid accumulation, or the expression of adipogenic and mitochondrial dynamics-related proteins, with the exception of phosphorylated Drp1 (Ser616), in differentiated 3T3-L1 adipocytes. The inhibition of mitochondrial fission did not affect adipocyte differentiation, while intracellular ROS production decreased in parallel with inhibition of adipocyte differentiation. Therefore, our results indicated that ROS are an essential regulator of adipocyte differentiation in 3T3-L1 cells.
[Mh] Termos MeSH primário: Dinaminas/antagonistas & inibidores
Radicais Livres/metabolismo
Insulina/farmacologia
Metabolismo dos Lipídeos
Quinazolinonas/farmacologia
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Células 3T3-L1
Adipócitos/citologia
Adipócitos/metabolismo
Animais
Antioxidantes/metabolismo
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone); 0 (Antioxidants); 0 (Free Radicals); 0 (Insulin); 0 (Quinazolinones); 0 (Reactive Oxygen Species); EC 3.6.5.5 (Dnm1l protein, mouse); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185764


  6 / 2016 MEDLINE  
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[PMID]:28957392
[Au] Autor:Mohanakrishnan A; Tran TVM; Kumar M; Chen H; Posner BA; Schmid SL
[Ad] Endereço:Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, United States of America.
[Ti] Título:A highly-sensitive high throughput assay for dynamin's basal GTPase activity.
[So] Source:PLoS One;12(9):e0185639, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clathrin-mediated endocytosis is the major pathway by which cells internalize materials from the external environment. Dynamin, a large multidomain GTPase, is a key regulator of clathrin-mediated endocytosis. It assembles at the necks of invaginated clathrin-coated pits and, through GTP hydrolysis, catalyzes scission and release of clathrin-coated vesicles from the plasma membrane. Several small molecule inhibitors of dynamin's GTPase activity, such as Dynasore and Dyngo-4a, are currently available, although their specificity has been brought into question. Previous screens for these inhibitors measured dynamin's stimulated GTPase activity due to lack of sufficient sensitivity, hence the mechanisms by which they inhibit dynamin are uncertain. We report a highly sensitive fluorescence-based assay capable of detecting dynamin's basal GTPase activity under conditions compatible with high throughput screening. Utilizing this optimized assay, we conducted a pilot screen of 8000 compounds and identified several "hits" that inhibit the basal GTPase activity of dynamin-1. Subsequent dose-response curves were used to validate the activity of these compounds. Interestingly, we found neither Dynasore nor Dyngo-4a inhibited dynamin's basal GTPase activity, although both inhibit assembly-stimulated GTPase activity. This assay provides the basis for a more extensive search for more potent and chemically desirable dynamin inhibitors.
[Mh] Termos MeSH primário: Dinaminas/metabolismo
GTP Fosfo-Hidrolases/metabolismo
Ensaios de Triagem em Larga Escala/métodos
[Mh] Termos MeSH secundário: Polarização de Fluorescência
Limite de Detecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185639


  7 / 2016 MEDLINE  
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[PMID]:28918902
[Au] Autor:Morita M; Prudent J; Basu K; Goyon V; Katsumura S; Hulea L; Pearl D; Siddiqui N; Strack S; McGuirk S; St-Pierre J; Larsson O; Topisirovic I; Vali H; McBride HM; Bergeron JJ; Sonenberg N
[Ad] Endereço:Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, Canada; Department of Molecular Medicine and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic addr
[Ti] Título:mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1.
[So] Source:Mol Cell;67(6):922-935.e5, 2017 Sep 21.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/fusion, ATP production, metabolite biogenesis, and apoptosis, are not well understood. Here, we demonstrate that the nutrient-sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin-related protein 1 (DRP1). Potent active-site mTOR inhibitors engender mitochondrial hyperfusion due to the diminished translation of MTFP1, which is mediated by translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for cell survival upon mTOR inhibition through mitochondrial hyperfusion employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions.
[Mh] Termos MeSH primário: Proteínas de Membrana/metabolismo
Mitocôndrias/enzimologia
Dinâmica Mitocondrial
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Apoptose
Sistemas CRISPR-Cas
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Linhagem Celular Tumoral
Sobrevivência Celular
Dinaminas/genética
Dinaminas/metabolismo
Fatores de Iniciação em Eucariotos/genética
Fatores de Iniciação em Eucariotos/metabolismo
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
Proteínas de Membrana/genética
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/ultraestrutura
Dinâmica Mitocondrial/efeitos dos fármacos
Complexos Multiproteicos/genética
Complexos Multiproteicos/metabolismo
Fosfoproteínas/genética
Fosfoproteínas/metabolismo
Fosforilação
Inibidores de Proteínas Quinases/farmacologia
Interferência de RNA
Transdução de Sinais
Serina-Treonina Quinases TOR/antagonistas & inibidores
Serina-Treonina Quinases TOR/genética
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Eif4ebp1 protein, mouse); 0 (Eif4ebp2 protein, mouse); 0 (Eukaryotic Initiation Factors); 0 (MTFP1 protein, mouse); 0 (Membrane Proteins); 0 (Multiprotein Complexes); 0 (Phosphoproteins); 0 (Protein Kinase Inhibitors); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 3.6.5.5 (Dnm1l protein, mouse); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE


  8 / 2016 MEDLINE  
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[PMID]:28855251
[Au] Autor:Fiuza M; Rostosky CM; Parkinson GT; Bygrave AM; Halemani N; Baptista M; Milosevic I; Hanley JG
[Ad] Endereço:Centre for Synaptic Plasticity and School of Biochemistry, University of Bristol, Bristol, England, UK.
[Ti] Título:PICK1 regulates AMPA receptor endocytosis via direct interactions with AP2 α-appendage and dynamin.
[So] Source:J Cell Biol;216(10):3323-3338, 2017 Oct 02.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clathrin-mediated endocytosis (CME) is used to internalize a diverse range of cargo proteins from the cell surface, often in response to specific signals. In neurons, the rapid endocytosis of GluA2-containing AMPA receptors (AMPARs) in response to NMDA receptor (NMDAR) stimulation causes a reduction in synaptic strength and is the central mechanism for long-term depression, which underlies certain forms of learning. The mechanisms that link NMDAR activation to CME of AMPARs remain elusive. PICK1 is a BAR domain protein required for NMDAR-dependent reductions in surface GluA2; however, the molecular mechanisms involved are unclear. In this study, we show that PICK1 makes direct, NMDAR-dependent interactions with the core endocytic proteins AP2 and dynamin. PICK1-AP2 interactions are required for clustering AMPARs at endocytic zones in dendrites in response to NMDAR stimulation and for consequent AMPAR internalization. We further show that PICK1 stimulates dynamin polymerization. We propose that PICK1 is a cargo-specific endocytic accessory protein required for efficient, activity-dependent AMPAR endocytosis.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/metabolismo
Proteínas de Transporte/metabolismo
Dinaminas/metabolismo
Endocitose/fisiologia
Proteínas Nucleares/metabolismo
Receptores de AMPA/metabolismo
Receptores de N-Metil-D-Aspartato/metabolismo
[Mh] Termos MeSH secundário: Complexo 2 de Proteínas Adaptadoras/genética
Animais
Proteínas de Transporte/genética
Dinaminas/genética
Células HEK293
Seres Humanos
Proteínas Nucleares/genética
Ratos
Ratos Wistar
Receptores de AMPA/genética
Receptores de N-Metil-D-Aspartato/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 2); 0 (Carrier Proteins); 0 (Nuclear Proteins); 0 (PICk1 protein, human); 0 (Prkcabp protein, rat); 0 (Receptors, AMPA); 0 (Receptors, N-Methyl-D-Aspartate); 0 (glutamate receptor ionotropic, AMPA 2); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201701034


  9 / 2016 MEDLINE  
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[PMID]:28787011
[Au] Autor:Stincardini C; Massignan T; Biggi S; Elezgarai SR; Sangiovanni V; Vanni I; Pancher M; Adami V; Moreno J; Stravalaci M; Maietta G; Gobbi M; Negro A; Requena JR; Castilla J; Nonno R; Biasini E
[Ad] Endereço:Dulbecco Telethon Laboratory of Prions and Amyloids, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
[Ti] Título:An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein.
[So] Source:PLoS One;12(8):e0182589, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrPC), an endogenous membrane glycoprotein of uncertain function, into PrPSc, a pathological isoform that replicates by imposing its abnormal folding onto PrPC molecules. A great deal of evidence supports the notion that PrPC plays at least two roles in prion diseases, by acting as a substrate for PrPSc replication, and as a mediator of its toxicity. This conclusion was recently supported by data suggesting that PrPC may transduce neurotoxic signals elicited by other disease-associated protein aggregates. Thus, PrPC may represent a convenient pharmacological target for prion diseases, and possibly other neurodegenerative conditions. Here, we sought to characterize the activity of chlorpromazine (CPZ), an antipsychotic previously shown to inhibit prion replication by directly binding to PrPC. By employing biochemical and biophysical techniques, we provide direct experimental evidence indicating that CPZ does not bind PrPC at biologically relevant concentrations. Instead, the compound exerts anti-prion effects by inducing the relocalization of PrPC from the plasma membrane. Consistent with these findings, CPZ also inhibits the cytotoxic effects delivered by a PrP mutant. Interestingly, we found that the different pharmacological effects of CPZ could be mimicked by two inhibitors of the GTPase activity of dynamins, a class of proteins involved in the scission of newly formed membrane vesicles, and recently reported as potential pharmacological targets of CPZ. Collectively, our results redefine the mechanism by which CPZ exerts anti-prion effects, and support a primary role for dynamins in the membrane recycling of PrPC, as well as in the propagation of infectious prions.
[Mh] Termos MeSH primário: Antipsicóticos/farmacologia
Clorpromazina/farmacologia
Proteínas Priônicas/metabolismo
[Mh] Termos MeSH secundário: Antipsicóticos/metabolismo
Linhagem Celular
Clorpromazina/metabolismo
Dinaminas/antagonistas & inibidores
Seres Humanos
Ligantes
Mutação
Proteínas Priônicas/genética
Transporte Proteico/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (Ligands); 0 (Prion Proteins); EC 3.6.5.5 (Dynamins); U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182589


  10 / 2016 MEDLINE  
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[PMID]:28724764
[Au] Autor:Liu CC; Zhang YN; Li ZY; Hou JX; Zhou J; Kan L; Zhou B; Chen PY
[Ad] Endereço:College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
[Ti] Título:Rab5 and Rab11 Are Required for Clathrin-Dependent Endocytosis of Japanese Encephalitis Virus in BHK-21 Cells.
[So] Source:J Virol;91(19), 2017 Oct 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During infection Japanese encephalitis virus (JEV) generally enters host cells via receptor-mediated clathrin-dependent endocytosis. The trafficking of JEV within endosomes is controlled by Rab GTPases, but which Rab proteins are involved in JEV entry into BHK-21 cells is unknown. In this study, entry and postinternalization of JEV were analyzed using biochemical inhibitors, RNA interference, and dominant negative (DN) mutants. Our data demonstrate that JEV entry into BHK-21 cells depends on clathrin, dynamin, and cholesterol but not on caveolae or macropinocytosis. The effect on JEV infection of dominant negative (DN) mutants of four Rab proteins that regulate endosomal trafficking was examined. Expression of DN Rab5 and DN Rab11, but not DN Rab7 and DN Rab9, significantly inhibited JEV replication. These results were further tested by silencing Rab5 or Rab11 expression before viral infection. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab11 within 15 min after virus entry, suggesting that after internalization JEV moves to early and recycling endosomes before the release of the viral genome. Our findings demonstrate the roles of Rab5 and Rab11 on JEV infection of BHK-21 cells through the endocytic pathway, providing new insights into the life cycle of flaviviruses. Although Japanese encephalitis virus (JEV) utilizes different endocytic pathways depending on the cell type being infected, the detailed mechanism of its entry into BHK-21 cells is unknown. Understanding the process of JEV endocytosis and postinternalization will advance our knowledge of JEV infection and pathogenesis as well as provide potential novel drug targets for antiviral intervention. With this objective, we used systematic approaches to dissect this process. The results show that entry of JEV into BHK-21 cells requires a low-pH environment and that the process occurs through dynamin-, actin-, and cholesterol-dependent clathrin-mediated endocytosis that requires Rab5 and Rab11. Our work provides a detailed picture of the entry of JEV into BHK-21 cells and the cellular events that follow.
[Mh] Termos MeSH primário: Clatrina/metabolismo
Vírus da Encefalite Japonesa (Espécie)/metabolismo
Endocitose/fisiologia
Internalização do Vírus
Proteínas rab de Ligação ao GTP/metabolismo
Proteínas rab5 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/metabolismo
Actinas/metabolismo
Animais
Caveolinas/metabolismo
Linhagem Celular
Membrana Celular/metabolismo
Colesterol/metabolismo
Cricetinae
Dinaminas/metabolismo
Encefalite Japonesa/patologia
Encefalite Japonesa/virologia
Interferência de RNA
RNA Interferente Pequeno/genética
Proteínas rab de Ligação ao GTP/genética
Proteínas rab5 de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Caveolins); 0 (Clathrin); 0 (RNA, Small Interfering); 97C5T2UQ7J (Cholesterol); EC 3.6.1.- (rab11 protein); EC 3.6.5.2 (rab GTP-Binding Proteins); EC 3.6.5.2 (rab5 GTP-Binding Proteins); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE



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