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Pesquisa : D12.776.543.512.249.500.500.700 [Categoria DeCS]
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  1 / 898 MEDLINE  
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[PMID]:28456331
[Au] Autor:Zdanowicz R; Kreutzberger A; Liang B; Kiessling V; Tamm LK; Cafiso DS
[Ad] Endereço:Department of Chemistry, University of Virginia, Charlottesville, Virginia; Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, Virginia.
[Ti] Título:Complexin Binding to Membranes and Acceptor t-SNAREs Explains Its Clamping Effect on Fusion.
[So] Source:Biophys J;113(6):1235-1250, 2017 Sep 19.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Complexin-1 is a SNARE effector protein that decreases spontaneous neurotransmitter release and enhances evoked release. Complexin binds to the fully assembled four-helical neuronal SNARE core complex as revealed in competing molecular models derived from x-ray crystallography. Presently, it is unclear how complexin binding to the postfusion complex accounts for its effects upon spontaneous and evoked release in vivo. Using a combination of spectroscopic and imaging methods, we characterize in molecular detail how complexin binds to the 1:1 plasma membrane t-SNARE complex of syntaxin-1a and SNAP-25 while simultaneously binding the lipid bilayer at both its N- and C-terminal ends. These interactions are cooperative, and binding to the prefusion acceptor t-SNARE complex is stronger than to the postfusion core complex. This complexin interaction reduces the affinity of synaptobrevin-2 for the 1:1 complex, thereby retarding SNARE assembly and vesicle docking in vitro. The results provide the basis for molecular models that account for the observed clamping effect of complexin beginning with the acceptor t-SNARE complex and the subsequent activation of the clamped complex by Ca and synaptotagmin.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Bicamadas Lipídicas/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Proteína 25 Associada a Sinaptossoma/metabolismo
Sintaxina 1/metabolismo
Proteína 2 Associada à Membrana da Vesícula/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/química
Proteínas Adaptadoras de Transporte Vesicular/genética
Animais
Escherichia coli
Bicamadas Lipídicas/química
Lipossomos/química
Lipossomos/metabolismo
Mutação
Proteínas do Tecido Nervoso/química
Proteínas do Tecido Nervoso/genética
Fosfatidilcolinas/química
Fosfatidilserinas/química
Ligação Proteica
Ratos
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Propriedades de Superfície
Proteína 25 Associada a Sinaptossoma/química
Sintaxina 1/química
Proteína 2 Associada à Membrana da Vesícula/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Lipid Bilayers); 0 (Liposomes); 0 (Nerve Tissue Proteins); 0 (Phosphatidylcholines); 0 (Phosphatidylserines); 0 (Recombinant Proteins); 0 (Snap25 protein, rat); 0 (Synaptosomal-Associated Protein 25); 0 (Syntaxin 1); 0 (Vamp2 protein, rat); 0 (Vesicle-Associated Membrane Protein 2); 0 (complexin I); 40290-44-6 (1-palmitoyl-2-oleoylglycero-3-phosphoserine); TE895536Y5 (1-palmitoyl-2-oleoylphosphatidylcholine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171212
[Lr] Data última revisão:
171212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


  2 / 898 MEDLINE  
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[PMID]:28607108
[Au] Autor:Fu J; Dai X; Plummer G; Suzuki K; Bautista A; Githaka JM; Senior L; Jensen M; Greitzer-Antes D; Manning Fox JE; Gaisano HY; Newgard CB; Touret N; MacDonald PE
[Ad] Endereço:Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
[Ti] Título:Kv2.1 Clustering Contributes to Insulin Exocytosis and Rescues Human ß-Cell Dysfunction.
[So] Source:Diabetes;66(7):1890-1900, 2017 Jul.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Insulin exocytosis is regulated by ion channels that control excitability and Ca influx. Channels also play an increasingly appreciated role in microdomain structure. In this study, we examine the mechanism by which the voltage-dependent K (Kv) channel Kv2.1 ( ) facilitates depolarization-induced exocytosis in INS 832/13 cells and ß-cells from human donors with and without type 2 diabetes (T2D). We find that Kv2.1, but not Kv2.2 ( ), forms clusters of 6-12 tetrameric channels at the plasma membrane and facilitates insulin exocytosis. Knockdown of Kv2.1 expression reduces secretory granule targeting to the plasma membrane. Expression of the full-length channel (Kv2.1-wild-type) supports the glucose-dependent recruitment of secretory granules. However, a truncated channel (Kv2.1-ΔC318) that retains electrical function and syntaxin 1A binding, but lacks the ability to form clusters, does not enhance granule recruitment or exocytosis. Expression of appears reduced in T2D islets, and further knockdown of does not inhibit Kv current in T2D ß-cells. Upregulation of Kv2.1-wild-type, but not Kv2.1-ΔC318, rescues the exocytotic phenotype in T2D ß-cells and increases insulin secretion from T2D islets. Thus, the ability of Kv2.1 to directly facilitate insulin exocytosis depends on channel clustering. Loss of this structural role for the channel might contribute to impaired insulin secretion in diabetes.
[Mh] Termos MeSH primário: Glicemia/metabolismo
Diabetes Mellitus Tipo 2/metabolismo
Exocitose
Células Secretoras de Insulina/metabolismo
Insulina/secreção
Vesículas Secretórias/metabolismo
Canais de Potássio Shab/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Estudos de Casos e Controles
Membrana Celular/metabolismo
Feminino
Técnicas de Silenciamento de Genes
Células HEK293
Seres Humanos
Células Secretoras de Insulina/secreção
Masculino
Meia-Idade
Sintaxina 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Insulin); 0 (KCNB1 protein, human); 0 (KCNB2 protein, human); 0 (STX1A protein, human); 0 (Shab Potassium Channels); 0 (Syntaxin 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.2337/db16-1170


  3 / 898 MEDLINE  
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[PMID]:28596237
[Au] Autor:Wheeler SE; Stacey HM; Nahaei Y; Hale SJ; Hardy AB; Reimann F; Gribble FM; Larraufie P; Gaisano HY; Brubaker PL
[Ad] Endereço:Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
[Ti] Título:The SNARE Protein Syntaxin-1a Plays an Essential Role in Biphasic Exocytosis of the Incretin Hormone Glucagon-Like Peptide 1.
[So] Source:Diabetes;66(9):2327-2338, 2017 Sep.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Exocytosis of the hormone glucagon-like peptide 1 (GLP-1) by the intestinal L cell is essential for the incretin effect after nutrient ingestion and is critical for the actions of dipeptidyl peptidase 4 inhibitors that enhance GLP-1 levels in patients with type 2 diabetes. Two-photon microscopy revealed that exocytosis of GLP-1 is biphasic, with a first peak at 1-6 min and a second peak at 7-12 min after stimulation with forskolin. Approximately 75% of the exocytotic events were represented by compound granule fusion, and the remainder were accounted for by full fusion of single granules under basal and stimulated conditions. The core SNARE protein syntaxin-1a (syn1a) was expressed by murine ileal L cells. At the single L-cell level, first-phase forskolin-induced exocytosis was reduced to basal ( < 0.05) and second-phase exocytosis abolished ( < 0.05) by syn1a knockout. L cells from intestinal-epithelial syn1a-deficient mice demonstrated a 63% reduction in forskolin-induced GLP-1 release in vitro ( < 0.001) and a 23% reduction in oral glucose-stimulated GLP-1 secretion ( < 0.05) in association with impairments in glucose-stimulated insulin release (by 60%; < 0.01) and glucose tolerance (by 20%; < 0.01). The findings identify an exquisite mechanism of metered secretory output that precisely regulates release of the incretin hormone GLP-1 and hence insulin secretion after a meal.
[Mh] Termos MeSH primário: Exocitose/fisiologia
Regulação da Expressão Gênica/fisiologia
Peptídeo 1 Semelhante ao Glucagon/metabolismo
Sintaxina 1/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Diabetes Mellitus Tipo 2/metabolismo
Células Enteroendócrinas/fisiologia
Feminino
Peptídeo 1 Semelhante ao Glucagon/genética
Peptídeo 1 Semelhante ao Glucagon/secreção
Glucose/metabolismo
Íleo/citologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Obesidade/metabolismo
Sintaxina 1/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Syntaxin 1); 89750-14-1 (Glucagon-Like Peptide 1); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170610
[St] Status:MEDLINE
[do] DOI:10.2337/db16-1403


  4 / 898 MEDLINE  
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[PMID]:28593826
[Au] Autor:Mao L; Wang H; Ma F; Guo Z; He H; Zhou H; Wang N
[Ad] Endereço:a Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology , Tianjin University of Science and Technology , Tianjin , P.R. China.
[Ti] Título:Exposure to static magnetic fields increases insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins.
[So] Source:Int J Radiat Biol;93(8):831-840, 2017 Aug.
[Is] ISSN:1362-3095
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To evaluate the effect of static magnetic fields (SMFs) on insulin secretion and explore the mechanisms underlying exposure to SMF-induced insulin secretion in rat insulinoma INS-1 cells. MATERIALS AND METHODS: INS-1 cells were exposed to a 400 mT SMF for 72 h, and the proliferation of INS-1 cells was detected by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The secretion of insulin was measured with an enzyme linked immunosorbent assays (ELISA), the expression of genes was detected by real-time PCR, and the expression of proteins was measured by Western blotting. RESULTS: Exposure to an SMF increased the expression and secretion of insulin by INS-1 cells but did not affect cell proliferation. Moreover, SMF exposure up-regulated the expression of several pancreas-specific transcriptional factors. Specifically, the activity of the rat insulin promoter was enhanced in INS-1 cells exposed to an SMF, and the expression levels of synaptosomal-associated protein 25 (SNAP-25) and syntaxin-1A were up-regulated after exposure to an SMF. CONCLUSIONS: SMF exposure can promote insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins.
[Mh] Termos MeSH primário: Insulina/genética
Insulina/secreção
Campos Magnéticos
Proteína 25 Associada a Sinaptossoma/metabolismo
Sintaxina 1/metabolismo
Ativação Transcricional
Regulação para Cima
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Células Secretoras de Insulina/secreção
Regiões Promotoras Genéticas/genética
Ratos
Proteína 25 Associada a Sinaptossoma/genética
Sintaxina 1/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (Synaptosomal-Associated Protein 25); 0 (Syntaxin 1); 0 (Transcription Factors)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM; S
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1080/09553002.2017.1332439


  5 / 898 MEDLINE  
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[PMID]:28559304
[Au] Autor:Nakayama T; Akagawa K
[Ad] Endereço:Department of Cell Physiology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan nakayama@ks.kyorin-u.ac.jp.
[Ti] Título:Transcription regulation mechanism of the syntaxin 1A gene via protein kinase A.
[So] Source:Biochem J;474(14):2465-2473, 2017 Jul 11.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Syntaxin 1A ( ) is primarily involved in the docking of synaptic vesicles at active zones in neurons. Its gene is a TATA-less gene, with several transcription initiation sites, which is activated by the binding of Sp1 and acetylated histone H3 (H3) in the core promoter region (CPR) through the derepression of class I histone deacetylase (HDAC). In the present study, to clarify the factor characterizing gene expression via the protein kinase A (PKA) pathway inducing the mRNA, we investigated whether the epigenetic process is involved in the gene transcription induced by PKA signaling. We found that the PKA activator forskolin induced expression in non-neuronal cells, FRSK and 3Y1, which do not endogenously express , unlike PC12. HDAC8 inhibition by shRNA knockdown and specific inhibitors induced expression in FRSK. The PKA inhibitor H89 suppressed HDAC8-Ser39 phosphorylation, H3 acetylation and induction by forskolin in FRSK cells. Finally, we also found that forskolin led to the dissociation of HDAC8-CPR interaction and the association of Sp1 and Ac-H3 to CPR in FRSK. The results of the current study suggest that forskolin phosphorylates HDAC8-Ser39 via the PKA pathway and increases histone H3 acetylation in cells expressing HDAC8, resulting in the induction of the gene.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Sintaxina 1/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Animais
Linhagem Celular
Colforsina/farmacologia
Ativadores de Enzimas/farmacologia
Inibidores de Histona Desacetilases/farmacologia
Histona Desacetilases/genética
Histona Desacetilases/metabolismo
Histonas/metabolismo
Fosforilação
Ratos
Transdução de Sinais
Sintaxina 1/genética
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Activators); 0 (Histone Deacetylase Inhibitors); 0 (Histones); 0 (Stx1a protein, rat); 0 (Syntaxin 1); 1F7A44V6OU (Colforsin); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.5.1.98 (Histone Deacetylases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170249


  6 / 898 MEDLINE  
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[PMID]:28515322
[Au] Autor:Zurawski Z; Page B; Chicka MC; Brindley RL; Wells CA; Preininger AM; Hyde K; Gilbert JA; Cruz-Rodriguez O; Currie KPM; Chapman ER; Alford S; Hamm HE
[Ad] Endereço:From the Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232-6600.
[Ti] Título:Gßγ directly modulates vesicle fusion by competing with synaptotagmin for binding to neuronal SNARE proteins embedded in membranes.
[So] Source:J Biol Chem;292(29):12165-12177, 2017 Jul 21.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:G -coupled G protein-coupled receptors can inhibit neurotransmitter release at synapses via multiple mechanisms. In addition to Gßγ-mediated modulation of voltage-gated calcium channels (VGCC), inhibition can also be mediated through the direct interaction of Gßγ subunits with the soluble -ethylmaleimide attachment protein receptor (SNARE) complex of the vesicle fusion apparatus. Binding studies with soluble SNARE complexes have shown that Gßγ binds to both ternary SNARE complexes, t-SNARE heterodimers, and monomeric SNAREs, competing with synaptotagmin 1(syt1) for binding sites on t-SNARE. However, in secretory cells, Gßγ, SNAREs, and synaptotagmin interact in the lipid environment of a vesicle at the plasma membrane. To approximate this environment, we show that fluorescently labeled Gßγ interacts specifically with lipid-embedded t-SNAREs consisting of full-length syntaxin 1 and SNAP-25B at the membrane, as measured by fluorescence polarization. Fluorescently labeled syt1 undergoes competition with Gßγ for SNARE-binding sites in lipid environments. Mutant Gßγ subunits that were previously shown to be more efficacious at inhibiting Ca -triggered exocytotic release than wild-type Gßγ were also shown to bind SNAREs at a higher affinity than wild type in a lipid environment. These mutant Gßγ subunits were unable to inhibit VGCC currents. Specific peptides corresponding to regions on Gß and Gγ shown to be important for the interaction disrupt the interaction in a concentration-dependent manner. In fusion assays using full-length t- and v-SNAREs embedded in liposomes, Gßγ inhibited Ca /synaptotagmin-dependent fusion. Together, these studies demonstrate the importance of these regions for the Gßγ-SNARE interaction and show that the target of Gßγ, downstream of VGCC, is the membrane-embedded SNARE complex.
[Mh] Termos MeSH primário: Subunidades beta da Proteína de Ligação ao GTP/metabolismo
Subunidades gama da Proteína de Ligação ao GTP/metabolismo
Bicamadas Lipídicas
Modelos Moleculares
Proteína 25 Associada a Sinaptossoma/metabolismo
Sinaptotagmina I/metabolismo
Sintaxina 1/metabolismo
[Mh] Termos MeSH secundário: Animais
Ligação Competitiva
Sinalização do Cálcio
Bovinos
Linhagem Celular
Subunidades beta da Proteína de Ligação ao GTP/química
Subunidades beta da Proteína de Ligação ao GTP/genética
Subunidades gama da Proteína de Ligação ao GTP/química
Subunidades gama da Proteína de Ligação ao GTP/genética
Seres Humanos
Lipossomos
Fusão de Membrana
Mutação
Proteínas do Tecido Nervoso/química
Proteínas do Tecido Nervoso/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Ratos
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Proteína 25 Associada a Sinaptossoma/química
Sinaptotagmina I/química
Sinaptotagmina I/genética
Sintaxina 1/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GTP-Binding Protein beta Subunits); 0 (GTP-Binding Protein gamma Subunits); 0 (Lipid Bilayers); 0 (Liposomes); 0 (Nerve Tissue Proteins); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (Snap25 protein, rat); 0 (Stx1a protein, rat); 0 (Synaptosomal-Associated Protein 25); 0 (Synaptotagmin I); 0 (Syntaxin 1); 0 (Syt1 protein, rat)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.773523


  7 / 898 MEDLINE  
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[PMID]:28495859
[Au] Autor:Lou X; Kim J; Hawk BJ; Shin YK
[Ad] Endereço:Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, U.S.A.
[Ti] Título:α-Synuclein may cross-bridge v-SNARE and acidic phospholipids to facilitate SNARE-dependent vesicle docking.
[So] Source:Biochem J;474(12):2039-2049, 2017 Jun 06.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Misfolded α-synuclein (A-syn) is widely recognized as the primal cause of neurodegenerative diseases including Parkinson's disease and dementia with Lewy bodies. The normal cellular function of A-syn has, however, been elusive. There is evidence that A-syn plays multiple roles in the exocytotic pathway in the neuron, but the underlying molecular mechanisms are unclear. A-syn has been known to interact with negatively charged phospholipids and with vesicle SNARE protein VAMP2. Using single-vesicle docking/fusion assays, we find that A-syn promotes SNARE-dependent vesicles docking significantly at 2.5 µM. When phosphatidylserine (PS) is removed from t-SNARE-bearing vesicles, the docking enhancement by A-syn disappears and A-syn instead acts as an inhibitor for docking. In contrast, subtraction of PS from the v-SNARE-carrying vesicles enhances vesicle docking even further. Moreover, when we truncate the C-terminal 45 residues of A-syn that participates in interacting with VAMP2, the promotion of vesicle docking is abrogated. Thus, the results suggest that the A-syn's interaction with v-SNARE through its C-terminal tail and its concurrent interaction with PS through its amphipathic N-terminal domain facilitate SNARE complex formation, whereby A-syn aids SNARE-dependent vesicle docking.
[Mh] Termos MeSH primário: Modelos Biológicos
Fosfatidilserinas/metabolismo
Proteínas SNARE/metabolismo
Vesículas Sinápticas/metabolismo
Proteína 25 Associada a Sinaptossoma/metabolismo
Proteína 2 Associada à Membrana da Vesícula/metabolismo
alfa-Sinucleína/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Seres Humanos
Lipossomos
Fusão de Membrana
Micelas
Mutagênese Sítio-Dirigida
Mutação
Proteínas do Tecido Nervoso/química
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Ratos
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas SNARE/química
Proteínas SNARE/genética
Proteína 25 Associada a Sinaptossoma/química
Proteína 25 Associada a Sinaptossoma/genética
Sinaptotagmina I/química
Sinaptotagmina I/genética
Sinaptotagmina I/metabolismo
Sintaxina 1/química
Sintaxina 1/genética
Sintaxina 1/metabolismo
Proteína 2 Associada à Membrana da Vesícula/química
Proteína 2 Associada à Membrana da Vesícula/genética
alfa-Sinucleína/química
alfa-Sinucleína/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Liposomes); 0 (Micelles); 0 (Nerve Tissue Proteins); 0 (Peptide Fragments); 0 (Phosphatidylserines); 0 (Recombinant Fusion Proteins); 0 (SNAP25 protein, human); 0 (SNARE Proteins); 0 (SNCA protein, human); 0 (STX1A protein, human); 0 (Synaptosomal-Associated Protein 25); 0 (Synaptotagmin I); 0 (Syntaxin 1); 0 (Syt1 protein, rat); 0 (VAMP2 protein, human); 0 (Vesicle-Associated Membrane Protein 2); 0 (alpha-Synuclein)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170200


  8 / 898 MEDLINE  
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[PMID]:28483813
[Au] Autor:Jakhanwal S; Lee CT; Urlaub H; Jahn R
[Ad] Endereço:Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
[Ti] Título:An activated Q-SNARE/SM protein complex as a possible intermediate in SNARE assembly.
[So] Source:EMBO J;36(12):1788-1802, 2017 Jun 14.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Assembly of the SNARE proteins syntaxin1, SNAP25, and synaptobrevin into a SNARE complex is essential for exocytosis in neurons. For efficient assembly, SNAREs interact with additional proteins but neither the nature of the intermediates nor the sequence of protein assembly is known. Here, we have characterized a ternary complex between syntaxin1, SNAP25, and the SM protein Munc18-1 as a possible acceptor complex for the R-SNARE synaptobrevin. The ternary complex binds synaptobrevin with fast kinetics, resulting in the rapid formation of a fully zippered SNARE complex to which Munc18-1 remains tethered by the N-terminal domain of syntaxin1. Intriguingly, only one of the synaptobrevin truncation mutants (Syb1-65) was able to bind to the syntaxin1:SNAP25:Munc18-1 complex, suggesting either a cooperative zippering mechanism that proceeds bidirectionally or the progressive R-SNARE binding via an SM template. Moreover, the complex is resistant to disassembly by NSF Based on these findings, we consider the ternary complex as a strong candidate for a physiological intermediate in SNARE assembly.
[Mh] Termos MeSH primário: Proteínas Munc18/metabolismo
Multimerização Proteica
Proteínas R-SNARE/metabolismo
Proteína 25 Associada a Sinaptossoma/metabolismo
Sintaxina 1/metabolismo
[Mh] Termos MeSH secundário: Animais
Camundongos
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Munc18 Proteins); 0 (R-SNARE Proteins); 0 (Snap25 protein, mouse); 0 (Stxbp1 protein, mouse); 0 (Synaptosomal-Associated Protein 25); 0 (Syntaxin 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201696270


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[PMID]:28348137
[Au] Autor:Santos TC; Wierda K; Broeke JH; Toonen RF; Verhage M
[Ad] Endereço:Department of Functional Genomics and.
[Ti] Título:Early Golgi Abnormalities and Neurodegeneration upon Loss of Presynaptic Proteins Munc18-1, Syntaxin-1, or SNAP-25.
[So] Source:J Neurosci;37(17):4525-4539, 2017 Apr 26.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The loss of presynaptic proteins Munc18-1, syntaxin-1, or SNAP-25 is known to produce cell death, but the underlying features have not been compared experimentally. Here, we investigated these features in cultured mouse CNS and DRG neurons. Side-by-side comparisons confirmed massive cell death, before synaptogenesis, within 1-4 DIV upon loss of t-SNAREs (syntaxin-1, SNAP-25) or Munc18-1, but not v-SNAREs (synaptobrevins/VAMP1/2/3 using tetanus neurotoxin (TeNT), also in TI-VAMP/VAMP7 knock-out (KO) neurons). A condensed Golgi was the first abnormality observed upon Munc18-1 or SNAP-25 loss within 3 DIV. This phenotype was distinct from the Golgi fragmentation observed in apoptosis. Cell death was too rapid after syntaxin-1 loss to study Golgi abnormalities. Syntaxin-1 and Munc18-1 depend on each other for normal cellular levels. We observed that endogenous syntaxin-1 accumulates at the Golgi of Munc18-1 KO neurons. However, expression of a non-neuronal Munc18 isoform that does not bind syntaxin-1, Munc18-3, in Munc18-1 KO neurons prevented cell death and restored normal Golgi morphology, but not synaptic transmission or syntaxin-1 targeting. Finally, we observed that DRG neurons are the only Munc18-1 KO neurons that do not degenerate or In these neurons, Golgi abnormalities were less severe, with no changes in Golgi shape. Together, these data demonstrate that cell death upon Munc18-1, syntaxin-1, or SNAP-25 loss occurs via a degenerative pathway unrelated to the known synapse function of these proteins and involving early Golgi abnormalities, distinct from apoptosis. This study provides new insights in a neurodegeneration pathway triggered by the absence of specific proteins involved in synaptic transmission (syntaxin-1, Munc18-1, SNAP-25), whereas other proteins involved in the same molecular process (synaptobrevins, Munc13-1/2) do not cause degeneration. Massive cell death occurs in cultured neurons upon depleting syntaxin-1, Munc18-1, and/or SNAP-25, well before synapse formation. This study characterizes several relevant cellular phenotypes, especially early Golgi abnormalities, distinct from abnormalities observed during apoptosis, and rules out several other phenotypes as causal (defects in syntaxin-1 targeting and synaptic transmission). As proteins, such as syntaxin-1, Munc18-1, or SNAP-25, modulate α-synuclein neuropathy and/or are dysregulated in Alzheimer's disease, understanding this type of neurodegeneration may provide new links between synaptic defects and neurodegeneration in humans.
[Mh] Termos MeSH primário: Complexo de Golgi/genética
Complexo de Golgi/metabolismo
Proteínas Munc18/genética
Doenças Neurodegenerativas/genética
Doenças Neurodegenerativas/metabolismo
Proteína 25 Associada a Sinaptossoma/genética
Sintaxina 1/genética
[Mh] Termos MeSH secundário: Animais
Apoptose
Morte Celular/genética
Células Cultivadas
Exocitose/genética
Complexo de Golgi/patologia
Camundongos
Camundongos Knockout
Doenças Neurodegenerativas/patologia
Sinapses/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Munc18 Proteins); 0 (Snap25 protein, mouse); 0 (Synaptosomal-Associated Protein 25); 0 (Syntaxin 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3352-16.2017


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[PMID]:28209294
[Au] Autor:Horigome T; Takumi S; Shirai K; Kido T; Hagiwara-Chatani N; Nakashima A; Adachi N; Yano H; Hirai Y
[Ad] Endereço:Department of Biomedical Chemistry, Graduate school of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan.
[Ti] Título:Sulfated glycosaminoglycans and non-classically secreted proteins, basic FGF and epimorphin, coordinately regulate TGF-ß-induced cell behaviors of human scar dermal fibroblasts.
[So] Source:J Dermatol Sci;86(2):132-141, 2017 May.
[Is] ISSN:1873-569X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Upon skin injuries, dermal fibroblasts actively produce transforming growth factor-ß (TGF-ß), which leads to the formation of α-smooth muscle actin (αSMA)-positive granulation tissues. The hyperplasia or incomplete regression of these tissues subsequently causes scar formation in the skin, where sulfated glycosaminoglycans (GAGs), side chains of unique proteoglycans, are supposed to play important roles. OBJECTIVE: The aim of this study is to clarify the effects of sulfated GAGs on dermal cell behaviors triggered by the TGF-ß signaling, along with its possible regulators basic fibroblast growth factor (bFGF) and cell surface epimorphin. bFGF and epimorphin might regulate the TGF-ß-induced αSMA expression, they could exert such effects only in specific cellular contexts, given that they lack conventional signal sequences for extracellular localization. METHODS: Human scar-derived dermal fibroblasts (HSFs) were treated with TGF-ß alone, TGF-ß plus bFGF, and TGF-ß plus cell surface expression of epimorphin. The effects of GAGs on the expression of αSMA and the cellular morphology were then investigated. RESULTS: A highly sulfated chondroitin sulfate (CS-E) or its substitute (heparinoid) had marked inhibitory effects on TGF-ß-mediated changes in HSF behaviors. We found that heparinoid can directly associate with TGF-ß, bFGF and epimorphin. We also found that bFGF downregulated αSMA, which was attenuated by heparinoid, whereas epimorphin augmented αSMA expression, which was further amplified by heparinoid. CONCLUSIONS: TGF-ß, bFGF and epimorphin in the extracellular microenvironment cooperatively affect HSF behaviors under the control of a highly sulfated chondroitin sulfate. These results provide important evidence towards understanding the regulation of TGF-ß-induced HSF behaviors.
[Mh] Termos MeSH primário: Cicatriz/metabolismo
Fibroblastos/metabolismo
Glicosaminoglicanos/química
Proteoglicanas/metabolismo
Sintaxina 1/metabolismo
Fator de Crescimento Transformador beta/farmacologia
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Células COS
Membrana Celular/metabolismo
Cercopithecus aethiops
Sulfatos de Condroitina/química
Fator 2 de Crescimento de Fibroblastos/farmacologia
Heparinoides/metabolismo
Seres Humanos
Proteínas Recombinantes/farmacologia
Transdução de Sinais
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Glycosaminoglycans); 0 (Heparinoids); 0 (Proteoglycans); 0 (Recombinant Proteins); 0 (STX2 protein, human); 0 (Syntaxin 1); 0 (Transforming Growth Factor beta); 103107-01-3 (Fibroblast Growth Factor 2); 9007-28-7 (Chondroitin Sulfates)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170218
[St] Status:MEDLINE



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