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[PMID]: 27777306 [Au] Autor: Sorrenson B; Cognard E; Lee KL; Dissanayake WC; Fu Y; Han W; Hughes WE; Shepherd PR [Ad] Endereço: From the Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. [Ti] Título: A Critical Role for ß-Catenin in Modulating Levels of Insulin Secretion from ß-Cells by Regulating Actin Cytoskeleton and Insulin Vesicle Localization. [So] Source: J Biol Chem;291(50):25888-25900, 2016 Dec 09. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic ß-cells are only partly understood. Here we investigate the involvement of ß-catenin in these processes. Reducing ß-catenin levels using siRNA knockdown attenuated GSIS in a range of ß-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both ß-cell models and isolated islets by short-term exposure to the ß-catenin inhibitory drug pyrvinium. In addition, short-term treatment with a drug that increases ß-catenin levels results in an increase in insulin secretion. The timing of these effects suggests that ß-catenin is required for the processes regulating trafficking and/or release of pre-existing insulin granules rather than for those regulated by gene expression. This was supported by the finding that the overexpression of the transcriptional co-activator of ß-catenin, transcription factor 7-like 2 (TCF7L2), attenuated insulin secretion, consistent with the extra TCF7L2 translocating ß-catenin from the plasma membrane pool to the nucleus. We show that ß-catenin depletion disrupts the intracellular actin cytoskeleton, and by using total internal reflectance fluorescence (TIRF) microscopy, we found that ß-catenin is required for the glucose- and incretin-induced depletion of insulin vesicles from near the plasma membrane. In conclusion, we find that ß-catenin levels modulate Ca -dependent insulin exocytosis under conditions of glucose, GLP-1, or KCl stimulation through a role in modulating insulin secretory vesicle localization and/or fusion via actin remodeling. These findings also provide insights as to how the overexpression of TCF7L2 may attenuate insulin secretion. [Mh] Termos MeSH primário: Citoesqueleto de Actina/metabolismo Células Secretoras de Insulina/secreção Insulina/secreção Vesículas Secretórias/secreção beta Catenina/metabolismo [Mh] Termos MeSH secundário: Citoesqueleto de Actina/genética Animais Linhagem Celular Peptídeo 1 Semelhante ao Glucagon/genética Peptídeo 1 Semelhante ao Glucagon/metabolismo Insulina/genética Células Secretoras de Insulina/citologia Camundongos Vesículas Secretórias/genética Proteína 2 Semelhante ao Fator 7 de Transcrição/genética Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo beta Catenina/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Insulin); 0 (Tcf7l2 protein, mouse); 0 (Transcription Factor 7-Like 2 Protein); 0 (beta Catenin); 89750-14-1 (Glucagon-Like Peptide 1) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 171209 [Lr] Data última revisão: 171209 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161026 [St] Status: MEDLINE

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[PMID]: 28765280 [Au] Autor: Kampmeyer C; Karakostova A; Schenstrøm SM; Abildgaard AB; Lauridsen AM; Jourdain I; Hartmann-Petersen R [Ad] Endereço: From the Linderstrøm-Lang Center, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark and. [Ti] Título: The exocyst subunit Sec3 is regulated by a protein quality control pathway. [So] Source: J Biol Chem;292(37):15240-15253, 2017 Sep 15. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Exocytosis involves fusion of secretory vesicles with the plasma membrane, thereby delivering membrane proteins to the cell surface and releasing material into the extracellular space. The tethering of the secretory vesicles before membrane fusion is mediated by the exocyst, an essential phylogenetically conserved octameric protein complex. Exocyst biogenesis is regulated by several processes, but the mechanisms by which the exocyst is degraded are unknown. Here, to unravel the components of the exocyst degradation pathway, we screened for extragenic suppressors of a temperature-sensitive fission yeast strain mutated in the exocyst subunit Sec3 ( ). One of the suppressing DNAs encoded a truncated dominant-negative variant of the 26S proteasome subunit, Rpt2, indicating that exocyst degradation is controlled by the ubiquitin-proteasome system. The temperature-dependent growth defect of the strain was gene dosage-dependent and suppressed by blocking the proteasome, Hsp70-type molecular chaperones, the Pib1 E3 ubiquitin-protein ligase, and the deubiquitylating enzyme Ubp3. Moreover, defects in cell septation, exocytosis, and endocytosis in mutant strains were similarly alleviated by mutation of components in this pathway. We also found that, particularly under stress conditions, wild-type Sec3 degradation is regulated by Pib1 and the 26S proteasome. In conclusion, our results suggest that a cytosolic protein quality control pathway monitors folding and proteasome-dependent turnover of an exocyst subunit and, thereby, controls exocytosis in fission yeast. [Mh] Termos MeSH primário: Enzimas Desubiquitinantes/metabolismo Endopeptidases/metabolismo Modelos Biológicos Proteínas de Schizosaccharomyces pombe/metabolismo Schizosaccharomyces/fisiologia Vesículas Secretórias/fisiologia Ubiquitina-Proteína Ligases/metabolismo Proteínas de Transporte Vesicular/metabolismo [Mh] Termos MeSH secundário: Enzimas Desubiquitinantes/antagonistas & inibidores Enzimas Desubiquitinantes/genética Endocitose/efeitos dos fármacos Endopeptidases/genética Inibidores Enzimáticos/farmacologia Exocitose/efeitos dos fármacos Deleção de Genes Proteínas de Choque Térmico HSP70/antagonistas & inibidores Proteínas de Choque Térmico HSP70/genética Proteínas de Choque Térmico HSP70/metabolismo Microscopia Eletrônica de Transmissão Mutação Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos Complexo de Endopeptidases do Proteassoma/genética Complexo de Endopeptidases do Proteassoma/metabolismo Complexo de Endopeptidases do Proteassoma/ultraestrutura Estabilidade Proteica/efeitos dos fármacos Proteólise/efeitos dos fármacos Proteínas Recombinantes de Fusão/química Proteínas Recombinantes de Fusão/metabolismo Schizosaccharomyces/efeitos dos fármacos Schizosaccharomyces/crescimento & desenvolvimento Schizosaccharomyces/ultraestrutura Proteínas de Schizosaccharomyces pombe/antagonistas & inibidores Proteínas de Schizosaccharomyces pombe/genética Vesículas Secretórias/efeitos dos fármacos Vesículas Secretórias/ultraestrutura Estresse Fisiológico/efeitos dos fármacos Temperatura Ambiente Ubiquitina-Proteína Ligases/antagonistas & inibidores Ubiquitina-Proteína Ligases/genética Ubiquitinação/efeitos dos fármacos Proteínas de Transporte Vesicular/antagonistas & inibidores Proteínas de Transporte Vesicular/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Enzyme Inhibitors); 0 (HSP70 Heat-Shock Proteins); 0 (Recombinant Fusion Proteins); 0 (Schizosaccharomyces pombe Proteins); 0 (Sec3 protein, S pombe); 0 (Vesicular Transport Proteins); 0 (sks2 protein, S pombe); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.4.- (Endopeptidases); EC 3.4.19.12 (Deubiquitinating Enzymes); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.4.99.- (rpt2 protein, S pombe) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170927 [Lr] Data última revisão: 170927 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170803 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M117.789867

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[PMID]: 28717032 [Au] Autor: Kuipers K; Jong WSP; van der Gaast-de Jongh CE; Houben D; van Opzeeland F; Simonetti E; van Selm S; de Groot R; Koenders MI; Azarian T; Pupo E; van der Ley P; Langereis JD; Zomer A; Luirink J; de Jonge MI [Ad] Endereço: Laboratory of Pediatric Infectious Diseases, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. [Ti] Título: Th17-Mediated Cross Protection against Pneumococcal Carriage by Vaccination with a Variable Antigen. [So] Source: Infect Immun;85(10), 2017 Oct. [Is] ISSN: 1098-5522 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Serotype-specific protection against is an important limitation of the current polysaccharide-based vaccines. To prevent serotype replacement, reduce transmission, and limit the emergence of new variants, it is essential to induce broad protection and restrict pneumococcal colonization. In this study, we used a prototype vaccine formulation consisting of lipopolysaccharide (LPS)-detoxified outer membrane vesicles (OMVs) from serovar Typhimurium displaying the variable N terminus of PspA (α1α2) for intranasal vaccination, which induced strong Th17 immunity associated with a substantial reduction of pneumococcal colonization. Despite the variable nature of this protein, a common major histocompatibility complex class (MHC-II) epitope was identified, based on prediction combined with screening, and was essential for interleukin-17 A (IL-17A)-mediated cross-reactivity and associated with cross protection. Based on 1,352 PspA sequences derived from a pneumococcal carriage cohort, this OMV-based vaccine formulation containing a single α1α2 type was estimated to cover 19.1% of strains, illustrating the potential of Th17-mediated cross protection. [Mh] Termos MeSH primário: Proteção Cruzada Interleucina-17/imunologia Infecções Pneumocócicas/prevenção & controle Vacinas Pneumocócicas/imunologia Salmonella typhimurium/química Streptococcus pneumoniae/imunologia Células Th17/imunologia [Mh] Termos MeSH secundário: Administração Intranasal Animais Antígenos de Bactérias/imunologia Antígenos de Bactérias/isolamento & purificação Proteínas da Membrana Bacteriana Externa/imunologia Proteínas de Bactérias/genética Proteínas de Bactérias/imunologia Simulação por Computador Epitopos/química Epitopos/genética Epitopos/imunologia Epitopos/isolamento & purificação Genes MHC Classe II Proteínas de Choque Térmico/genética Proteínas de Choque Térmico/imunologia Interleucina-17/biossíntese Lipopolissacarídeos/imunologia Camundongos Infecções Pneumocócicas/imunologia Vacinas Pneumocócicas/química Salmonella typhimurium/imunologia Vesículas Secretórias/química Vesículas Secretórias/imunologia Vacinação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, Bacterial); 0 (Bacterial Outer Membrane Proteins); 0 (Bacterial Proteins); 0 (Epitopes); 0 (Heat-Shock Proteins); 0 (Interleukin-17); 0 (Lipopolysaccharides); 0 (Pneumococcal Vaccines); 0 (phage shock protein, Bacteria) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171017 [Lr] Data última revisão: 171017 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170719 [St] Status: MEDLINE

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[PMID]: 28679628 [Au] Autor: Alenkvist I; Gandasi NR; Barg S; Tengholm A [Ad] Endereço: Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden. [Ti] Título: Recruitment of Epac2A to Insulin Granule Docking Sites Regulates Priming for Exocytosis. [So] Source: Diabetes;66(10):2610-2622, 2017 Oct. [Is] ISSN: 1939-327X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Epac is a cAMP-activated guanine nucleotide exchange factor that mediates cAMP signaling in various types of cells, including ß-cells, where it is involved in the control of insulin secretion. Upon activation, the protein redistributes to the plasma membrane, but the underlying molecular mechanisms and functional consequences are unclear. Using quantitative high-resolution microscopy, we found that cAMP elevation caused rapid binding of Epac2A to the ß-cell plasma membrane, where it accumulated specifically at secretory granules and rendered them more prone to undergo exocytosis. cAMP-dependent membrane binding required the high-affinity cyclic nucleotide-binding (CNB) and Ras association domains, but not the disheveled-Egl-10-pleckstrin domain. Although the N-terminal low-affinity CNB domain (CNB-A) was dispensable for the translocation to the membrane, it was critical for directing Epac2A to the granule sites. Epac1, which lacks the CNB-A domain, was recruited to the plasma membrane but did not accumulate at granules. We conclude that Epac2A controls secretory granule release by binding to the exocytosis machinery, an effect that is enhanced by prior cAMP-dependent accumulation of the protein at the plasma membrane. [Mh] Termos MeSH primário: Fatores de Troca do Nucleotídeo Guanina/química Fatores de Troca do Nucleotídeo Guanina/metabolismo Insulina/metabolismo [Mh] Termos MeSH secundário: Idoso Animais Linhagem Celular Tumoral Membrana Celular/metabolismo Células Cultivadas AMP Cíclico/metabolismo Exocitose/efeitos dos fármacos Feminino Peptídeo 1 Semelhante ao Glucagon/farmacologia Fatores de Troca do Nucleotídeo Guanina/genética Seres Humanos Células Secretoras de Insulina/efeitos dos fármacos Células Secretoras de Insulina/metabolismo Masculino Camundongos Meia-Idade Ligação Proteica Vesículas Secretórias/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Guanine Nucleotide Exchange Factors); 0 (Insulin); 0 (Rapgef4 protein, mouse); 89750-14-1 (Glucagon-Like Peptide 1); E0399OZS9N (Cyclic AMP) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171002 [Lr] Data última revisão: 171002 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170707 [St] Status: MEDLINE [do] DOI: 10.2337/db17-0050

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[PMID]: 28669852 [Au] Autor: Lasic E; Stenovec M; Kreft M; Robinson PJ; Zorec R [Ad] Endereço: Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia. [Ti] Título: Dynamin regulates the fusion pore of endo- and exocytotic vesicles as revealed by membrane capacitance measurements. [So] Source: Biochim Biophys Acta;1861(9):2293-2303, 2017 09. [Is] ISSN: 0006-3002 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: BACKGROUND: Dynamin is a multidomain GTPase exhibiting mechanochemical and catalytic properties involved in vesicle scission from the plasmalemma during endocytosis. New evidence indicates that dynamin is also involved in exocytotic release of catecholamines, suggesting the existence of a dynamin-regulated structure that couples endo- to exocytosis. METHODS: Thus we here employed high-resolution cell-attached capacitance measurements and super-resolution structured illumination microscopy to directly examine single vesicle interactions with the plasmalemma in cultured rat astrocytes treated with distinct pharmacological modulators of dynamin activity. Fluorescent dextrans and the lipophilic plasmalemmal marker DiD were utilized to monitor uptake and distribution of vesicles in the peri-plasmalemmal space and in the cell cytosol. RESULTS: Dynamin inhibition with Dynole™-34-2 and Dyngo™-4a prevented vesicle internalization into the cytosol and decreased fusion pore conductance of vesicles that remained attached to the plasmalemma via a narrow fusion pore that lapsed into a state of repetitive opening and closing - flickering. In contrast, the dynamin activator Ryngo™-1-23 promoted vesicle internalization and favored fusion pore closure by prolonging closed and shortening open fusion pore dwell times. Immunocytochemical staining revealed dextran uptake into dynamin-positive vesicles and increased dextran uptake into Syt4- and VAMP2-positive vesicles after dynamin inhibition, indicating prolonged retention of these vesicles at the plasmalemma. CONCLUSIONS: Our results have provided direct evidence for a role of dynamin in regulation of fusion pore geometry and kinetics of endo- and exocytotic vesicles, indicating that both share a common dynamin-regulated structural intermediate, the fusion pore. [Mh] Termos MeSH primário: Dinaminas/fisiologia Endocitose Exocitose Fusão de Membrana Vesículas Secretórias/fisiologia [Mh] Termos MeSH secundário: Animais Células Cultivadas Dextranos/farmacocinética Dinaminas/antagonistas & inibidores Capacitância Elétrica Feminino Ratos Ratos Wistar [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Dextrans); EC 3.6.5.5 (Dynamins) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171108 [Lr] Data última revisão: 171108 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170704 [St] Status: MEDLINE

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[PMID]: 28642299 [Au] Autor: Tranah TH; Vijay GKM; Ryan JM; Abeles RD; Middleton PK; Shawcross DL [Ad] Endereço: Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, United Kingdom. [Ti] Título: Dysfunctional neutrophil effector organelle mobilization and microbicidal protein release in alcohol-related cirrhosis. [So] Source: Am J Physiol Gastrointest Liver Physiol;313(3):G203-G211, 2017 Sep 01. [Is] ISSN: 1522-1547 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Patients with alcohol-related cirrhosis (ALD) are prone to infection. Circulating neutrophils in ALD are dysfunctional and predict development of sepsis, organ dysfunction, and survival. Neutrophil granules are important effector organelles containing a toxic array of microbicidal proteins, whose controlled release is required to kill microorganisms while minimizing inflammation and damage to host tissue. We investigated the role of these granular responses in contributing to immune disarray in ALD. Neutrophil granular content and mobilization were measured by flow cytometric quantitation of cell-surface/intracellular markers, [secretory vesicles (CD11b), secondary granules (CD66b), and primary granules (CD63; myeloperoxidase)] before and after bacterial stimulation in 29 patients with ALD cirrhosis (15 abstinent; 14 actively drinking) compared with healthy controls (HC). ImageStream Flow Cytometry characterized localization of granule subsets within the intracellular and cell-surface compartments. The plasma cytokine environment was analyzed using ELISA/cytokine bead array. Circulating neutrophils were primed in the resting state with upregulated surface expression of CD11b ( = 0.0001) in a cytokine milieu rich in IL-8 ( < 0.001) and lactoferrin ( = 0.035). Neutrophils showed exaggerated mobilization to the cell surface of primary granules at baseline ( = 0.001) and in response to -formyl-l-methionyl-l-leucyl-l-phenylalanine ( = 0.009) and ( = 0.0003) in ALD. There was no deficit in granule content or mobilization to the cell membrane in any granule subset observed. Paradoxically, active alcohol consumption abrogated the hyperresponsive neutrophil granular responses compared with their abstinent counterparts. Neutrophils are preprimed at baseline with augmented effector organelle mobilization in response to bacterial stimulation; neutrophil degranulation is not a mechanism leading to innate immunoparesis in ALD. Neutrophil granule release is dysregulated in patients with alcohol-related cirrhosis (ALD) with augmented effector organelle mobilization and microbiocidal protein release. Neutrophil granules are upregulated in ALD at baseline and demonstrate augmented responses to bacterial challenge. The granular responses in ALD did not contribute to the observed functional deficit in innate immunity but rather were dysregulated and hyperresponsive, which may induce bystander damage to host tissue. Paradoxically, active alcohol consumption abrogated the excessive neutrophil granular responses to bacterial stimulus compared with their abstinent counterparts. [Mh] Termos MeSH primário: Peptídeos Catiônicos Antimicrobianos/metabolismo Cirrose Hepática Alcoólica/patologia Neutrófilos/fisiologia [Mh] Termos MeSH secundário: Adulto Estudos de Casos e Controles Feminino Regulação da Expressão Gênica Seres Humanos Cirrose Hepática Alcoólica/metabolismo Masculino Meia-Idade Vesículas Secretórias/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antimicrobial Cationic Peptides) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171005 [Lr] Data última revisão: 171005 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170624 [St] Status: MEDLINE [do] DOI: 10.1152/ajpgi.00112.2016

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[PMID]: 28626002 [Au] Autor: Sørensen JB [Ad] Endereço: Center for Neuroscience, University of Copenhagen, Copenhagen, Denmark jakobbs@sund.ku.dk. [Ti] Título: Ride the wave: Retrograde trafficking becomes Ca dependent with BAIAP3. [So] Source: J Cell Biol;216(7):1887-1889, 2017 Jul 03. [Is] ISSN: 1540-8140 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The functions of four of the five proteins in the mammalian uncoordinated-13 (Munc13) family have been identified as priming factors in SNARE-dependent exocytosis. In this issue, Zhang et al. (2017. https://doi.org/10.1083/jcb.201702099) show that the fifth member, BAIAP3 (brain-specific angiogenesis inhibitor I-associated protein 3), acts in retrograde trafficking by returning secretory vesicle material to the trans-Golgi network. In its absence, secretory vesicle formation is impaired, leading to accumulation of immature vesicles, or lysosomal vesicle degradation. [Mh] Termos MeSH primário: Exocitose Vesículas Secretórias [Mh] Termos MeSH secundário: Animais Transporte Proteico Proteínas SNARE Rede trans-Golgi [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (SNARE Proteins) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171026 [Lr] Data última revisão: 171026 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170620 [St] Status: MEDLINE [do] DOI: 10.1083/jcb.201706007

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[PMID]: 28626000 [Au] Autor: Zhang X; Jiang S; Mitok KA; Li L; Attie AD; Martin TFJ [Ad] Endereço: Department of Biochemistry, University of Wisconsin, Madison, WI. [Ti] Título: BAIAP3, a C2 domain-containing Munc13 protein, controls the fate of dense-core vesicles in neuroendocrine cells. [So] Source: J Cell Biol;216(7):2151-2166, 2017 Jul 03. [Is] ISSN: 1540-8140 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Dense-core vesicle (DCV) exocytosis is a SNARE (soluble -ethylmaleimide-sensitive fusion attachment protein receptor)-dependent anterograde trafficking pathway that requires multiple proteins for regulation. Several C2 domain-containing proteins are known to regulate Ca -dependent DCV exocytosis in neuroendocrine cells. In this study, we identified others by screening all (∼139) human C2 domain-containing proteins by RNA interference in neuroendocrine cells. 40 genes were identified, including several encoding proteins with known roles (CAPS [calcium-dependent activator protein for secretion 1], Munc13-2, RIM1, and SYT10) and many with unknown roles. One of the latter, BAIAP3, is a secretory cell-specific Munc13-4 paralog of unknown function. BAIAP3 knockdown caused accumulation of fusion-incompetent DCVs in BON neuroendocrine cells and lysosomal degradation (crinophagy) of insulin-containing DCVs in INS-1 ß cells. BAIAP3 localized to endosomes was required for Golgi trans-Golgi network 46 (TGN46) recycling, exhibited Ca -stimulated interactions with TGN SNAREs, and underwent Ca -stimulated TGN recruitment. Thus, unlike other Munc13 proteins, BAIAP3 functions indirectly in DCV exocytosis by affecting DCV maturation through its role in DCV protein recycling. Ca rises that stimulate DCV exocytosis may stimulate BAIAP3-dependent retrograde trafficking to maintain DCV protein homeostasis and DCV function. [Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo Exocitose Proteínas do Tecido Nervoso/metabolismo Células Neuroendócrinas/metabolismo Vesículas Secretórias/metabolismo [Mh] Termos MeSH secundário: Animais Sinalização do Cálcio Proteínas de Transporte/genética Linhagem Celular Tumoral Células HEK293 Seres Humanos Insulina/metabolismo Insulina/secreção Células Secretoras de Insulina/metabolismo Células Secretoras de Insulina/secreção Proteínas do Tecido Nervoso/genética Células Neuroendócrinas/secreção Domínios Proteicos Transporte Proteico Interferência de RNA Ratos Vesículas Secretórias/secreção Transfecção Rede trans-Golgi/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (BAIAP3 protein, human); 0 (BAIAP3 protein, rat); 0 (Carrier Proteins); 0 (Insulin); 0 (Nerve Tissue Proteins) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170913 [Lr] Data última revisão: 170913 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170620 [St] Status: MEDLINE [do] DOI: 10.1083/jcb.201702099

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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

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MEDLINE

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[PMID]: 28600434 [Au] Autor: Milberg O; Shitara A; Ebrahim S; Masedunskas A; Tora M; Tran DT; Chen Y; Conti MA; Adelstein RS; Ten Hagen KG; Weigert R [Ad] Endereço: Intracellular Membrane Trafficking Section, National Institutes of Health, Bethesda, MD. [Ti] Título: Concerted actions of distinct nonmuscle myosin II isoforms drive intracellular membrane remodeling in live animals. [So] Source: J Cell Biol;216(7):1925-1936, 2017 Jul 03. [Is] ISSN: 1540-8140 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Membrane remodeling plays a fundamental role during a variety of biological events. However, the dynamics and the molecular mechanisms regulating this process within cells in mammalian tissues in situ remain largely unknown. In this study, we use intravital subcellular microscopy in live mice to study the role of the actomyosin cytoskeleton in driving the remodeling of membranes of large secretory granules, which are integrated into the plasma membrane during regulated exocytosis. We show that two isoforms of nonmuscle myosin II, NMIIA and NMIIB, control distinct steps of the integration process. Furthermore, we find that F-actin is not essential for the recruitment of NMII to the secretory granules but plays a key role in the assembly and activation of NMII into contractile filaments. Our data support a dual role for the actomyosin cytoskeleton in providing the mechanical forces required to remodel the lipid bilayer and serving as a scaffold to recruit key regulatory molecules. [Mh] Termos MeSH primário: Células Acinares/metabolismo Membrana Celular/metabolismo Exocitose Membranas Intracelulares/metabolismo Fusão de Membrana Miosina não Muscular Tipo IIA/metabolismo Miosina não Muscular Tipo IIB/metabolismo Glândulas Salivares/metabolismo Vesículas Secretórias/metabolismo [Mh] Termos MeSH secundário: Células Acinares/secreção Citoesqueleto de Actina/metabolismo Actinas/metabolismo Actomiosina/metabolismo Animais Proteínas de Drosophila/genética Proteínas de Drosophila/metabolismo Drosophila melanogaster/genética Drosophila melanogaster/metabolismo Genótipo Microscopia Intravital Cinética Camundongos Endogâmicos C57BL Camundongos Transgênicos Microscopia de Fluorescência Microscopia de Vídeo Miosina não Muscular Tipo IIA/genética Miosina não Muscular Tipo IIB/genética Fenótipo Glândulas Salivares/citologia Glândulas Salivares/secreção Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE; VIDEO-AUDIO MEDIA [Nm] Nome de substância: 0 (Actins); 0 (Drosophila Proteins); 9013-26-7 (Actomyosin); EC 3.6.1.- (Nonmuscle Myosin Type IIA); EC 3.6.1.- (Nonmuscle Myosin Type IIB) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170913 [Lr] Data última revisão: 170913 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170611 [St] Status: MEDLINE [do] DOI: 10.1083/jcb.201612126

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