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  1 / 2408 MEDLINE  
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[PMID]:28456783
[Au] Autor:Cai S; Li Y; Bai JY; Zhang ZQ; Wang Y; Qiao YB; Zhou XZ; Yang B; Tian Y; Cao C
[Ad] Endereço:Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
[Ti] Título:Gαi3 nuclear translocation causes irradiation resistance in human glioma cells.
[So] Source:Oncotarget;8(21):35061-35068, 2017 May 23.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have previously shown that Gαi3 is elevated in human glioma, mediating Akt activation and cancer cell proliferation. Here, we imply that Gαi3 could also be important for irradiation resistance. In A172 human glioma cells, Gαi3 knockdown (by targeted shRNAs) or dominant-negative mutation significantly potentiated irradiation-induced cell apoptosis. Reversely, forced over-expression of wild-type or constitutively-active Gαi3 inhibited irradiation-induced A172 cell apoptosis. Irradiation in A172 cells induced Gαi3 translocation to cell nuclei and association with local protein DNA-dependent protein kinase (DNA-PK) catalytic subunit. This association was important for DNA damage repair. Gαi3 knockdown, depletion (using Gαi3 knockout MEFs) or dominant-negative mutation potentiated irradiation-induced DNA damages. On the other hand, expression of the constitutively-active Gαi3 in A172 cells inhibited DNA damage by irradiation. Together, these results indicate a novel function of Gαi3 in irradiation-resistance in human glioma cells.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Glioma/metabolismo
Tolerância a Radiação
[Mh] Termos MeSH secundário: Neoplasias Encefálicas/genética
Neoplasias Encefálicas/radioterapia
Linhagem Celular Tumoral
Núcleo Celular/metabolismo
Dano ao DNA
Proteína Quinase Ativada por DNA/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética
Regulação Neoplásica da Expressão Gênica/efeitos da radiação
Glioma/genética
Glioma/radioterapia
Seres Humanos
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 3.6.5.1 (GNAI3 protein, human); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.17043


  2 / 2408 MEDLINE  
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[PMID]:29381923
[Au] Autor:Yang Y; Chu FH; Xu WR; Sun JQ; Sun X; Ma XM; Yu MW; Yang GW; Wang XM
[Ad] Endereço:Department of Oncology, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University.
[Ti] Título:Identification of regulatory role of DNA methylation in colon cancer gene expression via systematic bioinformatics analysis.
[So] Source:Medicine (Baltimore);96(47):e8487, 2017 Nov.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Colon cancer arises from the accumulations of genetic and epigenetic changes. Currently, profiles of DNA methylation and gene expression of colon cancer have not been elucidated clearly. This articles aims to characterize the profile of DNA methylation and gene expression of colon cancer systemically, and acquire candidate genes potentially regulated by altered methylation for this disease.Data were downloaded from The Cancer Genome Atlas database. Differentially methylated CpG sites (DMCs) and differentially methylated regions (DMRs) were calculated via COHCAP. Differentially expressed genes (DEGs) were identified by DESeq2. Weighted gene co-expression network analysis (WGCNA) package in R was applied for WGCNA.Data of 275 solid tumor tissues and 19 adjacent tumor tissues of colon cancer were obtained. A total of 1828 DMCs, including 1390 hypermethylated and 438 hypomethylated CpG sites, were identified between tumor and normal groups. A total of 789 DEGs, containing 435 upregulated genes and 354 downregulated genes were observed. It revealed that 8 DMRs-DEGs and 95 DMCs-DEGs pairs were significantly correlated. Furthermore, genes of yellow and brown modules from WGCNA were significantly correlated with tumor/normal status, and significantly enriched in peroxisome proliferator activated receptor signaling pathway, glutamatergic synapse, and neuroactive ligand-receptor interaction. Genes in the above 2 modules were also significantly enriched in DMCs or DMRs-associated genes. Specifically, ADHFE1, HAND2, and GNAO1 were hypermethylated and downregulated in colon cancer, suggesting that the low expression levels of these genes may be regulated by DNA hypermethylation. In addition, the 3 genes were involved in brown module of WGCNA, indicating their important roles in colon cancer.The investigation of the relationship between DNA methylation and gene expression may help to understand the effect of DNA methylation alteration on genes expression, especially gene co-expression network in the development of colon cancer. Genes such as ADHFE1, HAND2, and GNAO1 may be served as potential candidates for diagnosis and therapy targets in colon cancer.
[Mh] Termos MeSH primário: Neoplasias do Colo/genética
Neoplasias do Colo/fisiopatologia
Metilação de DNA/fisiologia
Expressão Gênica/fisiologia
[Mh] Termos MeSH secundário: Oxirredutases do Álcool/metabolismo
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Ilhas de CpG/fisiologia
Bases de Dados Genéticas
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Redes Reguladoras de Genes/fisiologia
Seres Humanos
Proteínas Mitocondriais/metabolismo
Receptores Ativados por Proliferador de Peroxissomo/metabolismo
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (GNAO1 protein, human); 0 (HAND2 protein, human); 0 (Mitochondrial Proteins); 0 (Peroxisome Proliferator-Activated Receptors); EC 1.1.- (Alcohol Oxidoreductases); EC 1.1.99.24 (hydroxyacid-oxoacid transhydrogenase); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000008487


  3 / 2408 MEDLINE  
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[PMID]:28450397
[Au] Autor:Gonzalez de Valdivia E; Broselid S; Kahn R; Olde B; Leeb-Lundberg LMF
[Ad] Endereço:From the Departments of Experimental Medical Science.
[Ti] Título:G protein-coupled estrogen receptor 1 (GPER1)/GPR30 increases ERK1/2 activity through PDZ motif-dependent and -independent mechanisms.
[So] Source:J Biol Chem;292(24):9932-9943, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor 1 (GPER1), is thought to play important roles in breast cancer and cardiometabolic regulation, but many questions remain about ligand activation, effector coupling, and subcellular localization. We showed recently that GPR30 interacts through the C-terminal type I PDZ motif with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, which anchor the receptor in the plasma membrane and mediate an apparently constitutive decrease in cAMP production independently of G Here, we show that GPR30 also constitutively increases ERK1/2 activity. Removing the receptor PDZ motif or knocking down specifically AKAP5 inhibited the increase, showing that this increase also requires the PDZ interaction. However, the increase was inhibited by pertussis toxin as well as by wortmannin but not by AG1478, indicating that G and phosphoinositide 3-kinase (PI3K) mediate the increase independently of epidermal growth factor receptor transactivation. FK506 and okadaic acid also inhibited the increase, implying that a protein phosphatase is involved. The proposed GPR30 agonist G-1 also increased ERK1/2 activity, but this increase was only observed at a level of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif did not inhibit the G-1-stimulated increase. Based on these results, we propose that GPR30 increases ERK1/2 activity via two G -mediated mechanisms, a PDZ-dependent, apparently constitutive mechanism and a PDZ-independent G-1-stimulated mechanism.
[Mh] Termos MeSH primário: Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/agonistas
Sistema de Sinalização das MAP Quinases
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Modelos Moleculares
Fosfatidilinositol 3-Quinase/metabolismo
Receptores Estrogênicos/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Ancoragem à Quinase A/antagonistas & inibidores
Proteínas de Ancoragem à Quinase A/genética
Proteínas de Ancoragem à Quinase A/metabolismo
Substituição de Aminoácidos
Ciclopentanos/farmacologia
Ativação Enzimática/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Células HEK293
Seres Humanos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Proteína Quinase 1 Ativada por Mitógeno/química
Proteína Quinase 1 Ativada por Mitógeno/genética
Proteína Quinase 3 Ativada por Mitógeno/química
Proteína Quinase 3 Ativada por Mitógeno/genética
Mutação
Domínios PDZ
Fosfatidilinositol 3-Quinase/química
Fosfatidilinositol 3-Quinase/genética
Fosforilação/efeitos dos fármacos
Processamento de Proteína Pós-Traducional/efeitos dos fármacos
Quinolinas/farmacologia
Interferência de RNA
Ensaio Radioligante
Receptores Estrogênicos/química
Receptores Estrogênicos/genética
Receptores Acoplados a Proteínas-G/agonistas
Receptores Acoplados a Proteínas-G/química
Receptores Acoplados a Proteínas-G/genética
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone); 0 (A Kinase Anchor Proteins); 0 (AKAP5 protein, human); 0 (Cyclopentanes); 0 (Enzyme Inhibitors); 0 (GPER protein, human); 0 (Quinolines); 0 (Receptors, Estrogen); 0 (Receptors, G-Protein-Coupled); 0 (Recombinant Fusion Proteins); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.24 (MAPK1 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171228
[Lr] Data última revisão:
171228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.765875


  4 / 2408 MEDLINE  
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[PMID]:28968387
[Au] Autor:Topalidou I; Cooper K; Pereira L; Ailion M
[Ad] Endereço:Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
[Ti] Título:Dopamine negatively modulates the NCA ion channels in C. elegans.
[So] Source:PLoS Genet;13(10):e1007032, 2017 Oct.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.
[Mh] Termos MeSH primário: Proteínas de Caenorhabditis elegans/metabolismo
Caenorhabditis elegans/efeitos dos fármacos
Caenorhabditis elegans/genética
Dopamina/farmacologia
Quinases de Receptores Acoplados a Proteína G/metabolismo
Canais Iônicos/metabolismo
[Mh] Termos MeSH secundário: Acetilcolina/metabolismo
Animais
Proteínas de Caenorhabditis elegans/genética
Epistasia Genética
Quinases de Receptores Acoplados a Proteína G/genética
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Regulação da Expressão Gênica
Estudo de Associação Genômica Ampla
Interneurônios/efeitos dos fármacos
Interneurônios/metabolismo
Canais Iônicos/genética
Oxigenases de Função Mista/genética
Oxigenases de Função Mista/metabolismo
Regiões Promotoras Genéticas
Receptores de Dopamina D2/genética
Receptores de Dopamina D2/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caenorhabditis elegans Proteins); 0 (DOP-3 protein, C elegans); 0 (GOA-1 protein, C elegans); 0 (Ion Channels); 0 (NCA-1 protein, C elegans); 0 (NCA-2 protein, C elegans); 0 (Receptors, Dopamine D2); 0 (cat-2 protein, C elegans); EC 1.- (Mixed Function Oxygenases); EC 2.7.11.16 (G-Protein-Coupled Receptor Kinases); EC 2.7.11.16 (GRK-2 protein, C elegans); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go); N9YNS0M02X (Acetylcholine); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007032


  5 / 2408 MEDLINE  
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[PMID]:28945785
[Au] Autor:Doijen J; Van Loy T; De Haes W; Landuyt B; Luyten W; Schoofs L; Schols D
[Ad] Endereço:Laboratory of Functional genomics & proteomics, Zoological Institute, KU Leuven, Belgium.
[Ti] Título:Signaling properties of the human chemokine receptors CXCR4 and CXCR7 by cellular electric impedance measurements.
[So] Source:PLoS One;12(9):e0185354, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The chemokine receptor 4 (CXCR4) and 7 (CXCR7) are G-protein-coupled receptors involved in various diseases including human cancer. As such, they have become important targets for therapeutic intervention. Cell-based receptor assays, able to detect agents that modulate receptor activity, are of key importance for drug discovery. We evaluated the potential of cellular electric impedance for this purpose. Dose-dependent and specific stimulation of CXCR4 was detected upon addition of its unique chemokine ligand CXCL12. The response magnitude correlated with the CXCR4 expression level. Gαi coupling and signaling contributed extensively to the impedance response, whereas Gαq- and Gßγ-related events had only minor effects on the impedance profile. CXCR7 signaling could not be detected using impedance measurements. However, increasing levels of CXCR7 expression significantly reduced the CXCR4-mediated impedance readout, suggesting a regulatory role for CXCR7 on CXCR4-mediated signaling. Taken together, cellular electric impedance spectroscopy can represent a valuable alternative pharmacological cell-based assay for the identification of molecules targeting CXCR4, but not for CXCR7 in the absence of CXCR4.
[Mh] Termos MeSH primário: Receptores CXCR4/metabolismo
Receptores CXCR/metabolismo
[Mh] Termos MeSH secundário: Sinalização do Cálcio
Linhagem Celular Tumoral
Quimiocina CXCL12/genética
Quimiocina CXCL12/metabolismo
Impedância Elétrica
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Células HT29
Seres Humanos
Ligantes
Toxina Pertussis/toxicidade
Receptores CXCR/genética
Receptores CXCR4/genética
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CXCL12 protein, human); 0 (CXCR4 protein, human); 0 (CXCR7 protein, human); 0 (Chemokine CXCL12); 0 (Ligands); 0 (Receptors, CXCR); 0 (Receptors, CXCR4); 0 (Recombinant Proteins); EC 2.4.2.31 (Pertussis Toxin); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185354


  6 / 2408 MEDLINE  
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[PMID]:28912160
[Au] Autor:Robinson SE; Sohal VS
[Ad] Endereço:Department of Psychiatry and Center for Integrative Neuroscience, Weill Institute for Neurosciences, and Kavli Institute for Fundamental Neuroscience, University of California-San Francisco, San Francisco, California 94143.
[Ti] Título:Dopamine D2 Receptors Modulate Pyramidal Neurons in Mouse Medial Prefrontal Cortex through a Stimulatory G-Protein Pathway.
[So] Source:J Neurosci;37(42):10063-10073, 2017 Oct 18.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dopaminergic modulation of prefrontal cortex (PFC) is thought to play key roles in many cognitive functions and to be disrupted in pathological conditions, such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically projecting (SC) pyramidal neurons within L5 of the PFC. These D2R-induced ADPs only occur following synaptic input, which activates NMDARs, even when the delay between the synaptic input and ADPs is relatively long (e.g., several hundred milliseconds). Here, we use a combination of electrophysiological, optogenetic, pharmacological, transgenic, and chemogenetic approaches to elucidate cellular mechanisms underlying this phenomenon in male and female mice. We find that knocking out D2Rs eliminates the ADP in a cell-autonomous fashion, confirming that this ADP depends on D2Rs. Hyperpolarizing current injection, but not AMPA receptor blockade, prevents synaptic stimulation from facilitating D2R-induced ADPs, suggesting that this phenomenon depends on the recruitment of voltage-dependent currents (e.g., NMDAR-mediated Ca influx) by synaptic input. Finally, the D2R-induced ADP is blocked by inhibitors of cAMP/PKA signaling, insensitive to pertussis toxin or ß-arrestin knock-out, and mimicked by G -DREADD stimulation, suggesting that D2R activation elicits the ADP by stimulating cAMP/PKA signaling. These results show that this unusual physiological phenomenon, in which D2Rs enhance cellular excitability in a manner that depends on synaptic input, is mediated at the cellular level through the recruitment of signaling pathways associated with G , rather than the G -associated mechanisms that have classically been ascribed to D2Rs. Dopamine D2 receptors (D2Rs) in the prefrontal cortex (PFC) are thought to play important roles in behaviors, including working memory and cognitive flexibility. Variation in D2Rs has also been implicated in schizophrenia, Tourette syndrome, and bipolar disorder. Recently, we described a new mechanism through which D2R activation can enhance the excitability of pyramidal neurons in the PFC. Here, we explore the underlying cellular mechanisms. Surprisingly, although D2Rs are classically assumed to signal through G -coupled G-proteins and/or scaffolding proteins, such as ß-arrestin, we find that the effects of D2Rs on prefrontal pyramidal neurons are actually mediated by pathways associated with G -mediated signaling. Furthermore, we show how, via this D2R-dependent phenomenon, synaptic input can enhance the excitability of prefrontal neurons over timescales on the order of seconds. These results elucidate cellular mechanisms underlying a novel signaling pathway downstream of D2Rs that may contribute to prefrontal function under normal and pathological conditions.
[Mh] Termos MeSH primário: Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia
Córtex Pré-Frontal/citologia
Córtex Pré-Frontal/fisiologia
Células Piramidais/fisiologia
Receptores de Dopamina D2/fisiologia
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
N-Metilaspartato/farmacologia
Técnicas de Cultura de Órgãos
Córtex Pré-Frontal/efeitos dos fármacos
Células Piramidais/efeitos dos fármacos
Quimpirol/farmacologia
Receptores de Dopamina D2/agonistas
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Dopamine D2); 20OP60125T (Quinpirole); 6384-92-5 (N-Methylaspartate); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1893-17.2017


  7 / 2408 MEDLINE  
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[PMID]:28892485
[Au] Autor:van Keulen SC; Rothlisberger U
[Ad] Endereço:Institut des Sciences et Ingénierie Chimiques, École Polytechnicque Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
[Ti] Título:Exploring the inhibition mechanism of adenylyl cyclase type 5 by n-terminal myristoylated Gαi1.
[So] Source:PLoS Comput Biol;13(9):e1005673, 2017 Sep.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adenylyl cyclase (AC) is an important messenger involved in G-protein-coupled-receptor signal transduction pathways, which is a well-known target for drug development. AC is regulated by activated stimulatory (Gαs) and inhibitory (Gαi) G proteins in the cytosol. Although experimental studies have shown that these Gα subunits can stimulate or inhibit AC's function in a non-competitive way, it is not well understood what the difference is in their mode of action as both Gα subunits appear structurally very similar in a non-lipidated state. However, a significant difference between Gαs and Gαi is that while Gαs does not require any lipidation in order to stimulate AC, N-terminal myristoylation is crucial for Gαi's inhibitory function as AC is not inhibited by non-myristoylated Gαi. At present, only the conformation of the complex including Gαs and AC has been resolved via X-ray crystallography. Therefore, understanding the interaction between Gαi and AC is important as it will provide more insight into the unknown mechanism of AC regulation. This study demonstrates via classical molecular dynamics simulations that the myristoylated Gαi1 structure is able to interact with apo adenylyl cyclase type 5 in a way that causes inhibition of the catalytic function of the enzyme, suggesting that Gα lipidation could play a crucial role in AC regulation and in regulating G protein function by affecting Gαi's active conformation.
[Mh] Termos MeSH primário: Adenilil Ciclases/química
Adenilil Ciclases/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Seres Humanos
Simulação de Dinâmica Molecular
Ácidos Mirísticos
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Myristic Acids); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go); EC 4.6.1.1 (Adenylyl Cyclases); EC 4.6.1.1 (adenylyl cyclase type V)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005673


  8 / 2408 MEDLINE  
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[PMID]:28803726
[Au] Autor:Solis GP; Bilousov O; Koval A; Lüchtenborg AM; Lin C; Katanaev VL
[Ad] Endereço:Department of Pharmacology and Toxicology, University of Lausanne, CH-1011 Lausanne, Switzerland. Electronic address: gonzalo.solis@unil.ch.
[Ti] Título:Golgi-Resident Gαo Promotes Protrusive Membrane Dynamics.
[So] Source:Cell;170(5):939-955.e24, 2017 Aug 24.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To form protrusions like neurites, cells must coordinate their induction and growth. The first requires cytoskeletal rearrangements at the plasma membrane (PM), the second requires directed material delivery from cell's insides. We find that the Gαo-subunit of heterotrimeric G proteins localizes dually to PM and Golgi across phyla and cell types. The PM pool of Gαo induces, and the Golgi pool feeds, the growing protrusions by stimulated trafficking. Golgi-residing KDELR binds and activates monomeric Gαo, atypically for G protein-coupled receptors that normally act on heterotrimeric G proteins. Through multidimensional screenings identifying > 250 Gαo interactors, we pinpoint several basic cellular activities, including vesicular trafficking, as being regulated by Gαo. We further find small Golgi-residing GTPases Rab1 and Rab3 as direct effectors of Gαo. This KDELR → Gαo → Rab1/3 signaling axis is conserved from insects to mammals and controls material delivery from Golgi to PM in various cells and tissues.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Extensões da Superfície Celular/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Complexo de Golgi/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Drosophila
Feminino
GTP Fosfo-Hidrolases/metabolismo
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Neuritos/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
Receptores de Peptídeos/metabolismo
Técnicas do Sistema de Duplo-Híbrido
Proteínas rab1 de Ligação ao GTP/metabolismo
Proteínas rab3 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); 0 (Receptors, Peptide); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go); EC 3.6.5.2 (rab1 GTP-Binding Proteins); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[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:170815
[St] Status:MEDLINE


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[PMID]:28760338
[Au] Autor:Zhu Y; Zhang L; Zhang XC; Zhao Y
[Ad] Endereço:National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
[Ti] Título:Structural dynamics of G α protein revealed by single molecule FRET.
[So] Source:Biochem Biophys Res Commun;491(3):603-608, 2017 Sep 23.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The heterotrimeric G proteins (Gαßγ) act as molecular switches to mediate signal transduction from G protein-coupled receptors to downstream effectors. Upon interaction with an activated receptor, G protein exchanges its bound GDP with GTP, stimulating downstream signal transmission. Release of GDP requires a structural rearrangement between the GTPase domain and helical domain of the Gα subunit. Here, we used single molecule fluorescence resonance energy transfer (smFRET) technique to study the conformational dynamics of these two domains in the apo state and in the binding of different ligands. Direct imaging of individual molecules showed that the G α subunit is highly dynamic, and at least three major conformations of G α could be observed in the apo state. Upon binding of GDP, G α becomes dramatically less dynamic, resulting in a closed conformation between the two domains. We postulate that changes between the three conformations are sequential, and the three conformations appear to have distinct affinities toward GDP.
[Mh] Termos MeSH primário: Transferência Ressonante de Energia de Fluorescência/métodos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/ultraestrutura
Guanosina Difosfato/química
Imagem Molecular/métodos
[Mh] Termos MeSH secundário: Sítios de Ligação
Ativação Enzimática
Ligação Proteica
Conformação Proteica
Domínios Proteicos
Subunidades Proteicas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Subunits); 146-91-8 (Guanosine Diphosphate); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE


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[PMID]:28692698
[Au] Autor:Sarkar O; Li Y; Anand-Srivastava MB
[Ad] Endereço:Department of Pharmacology and Physiology, Faculty of Medicine, University of Montréal, Montréal, Canada.
[Ti] Título:Nitric oxide attenuates overexpression of Giα proteins in vascular smooth muscle cells from SHR: Role of ROS and ROS-mediated signaling.
[So] Source:PLoS One;12(7):e0179301, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit decreased levels of nitric oxide (NO) that may be responsible for the overexpression of Giα proteins that has been shown as a contributing factor for the pathogenesis of hypertension in SHR. The present study was undertaken to investigate if increasing the intracellular levels of NO by NO donor S-Nitroso-N-acetyl-DL-penicillamine (SNAP) could attenuate the enhanced expression of Giα proteins in VSMC from SHR and explore the underlying mechanisms responsible for this response. The expression of Giα proteins and phosphorylation of ERK1/2, growth factor receptors and c-Src was determined by Western blotting using specific antibodies. Treatment of VSMC from SHR with SNAP for 24 hrs decreased the enhanced expression of Giα-2 and Giα-3 proteins and hyperproliferation that was not reversed by 1H (1, 2, 4) oxadiazole (4, 3-a) quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase, however, PD98059, a MEK inhibitor restored the SNAP-induced decreased expression of Giα proteins towards control levels. In addition, the increased production of superoxide anion, NAD(P)H oxidase activity, overexpression of AT1 receptor, Nox4, p22phox and p47phox proteins, enhanced levels of TBARS and protein carbonyl, increased phosphorylation of PDGF-R, EGF-R, c-Src and ERK1/2 in VSMC from SHR were all decreased to control levels by SNAP treatment. These results suggest that NO decreased the enhanced expression of Giα-2/3 proteins and hyperproliferation of VSMC from SHR by cGMP-independent mechanism and involves ROS and ROS-mediated transactivation of EGF-R/PDGF-R and MAP kinase signaling pathways.
[Mh] Termos MeSH primário: Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Músculo Liso Vascular/citologia
Miócitos de Músculo Liso/metabolismo
Óxido Nítrico/farmacologia
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
GMP Cíclico/análogos & derivados
GMP Cíclico/farmacologia
DNA/biossíntese
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Flavonoides/farmacologia
Masculino
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/enzimologia
NADPH Oxidases/metabolismo
Doadores de Óxido Nítrico/farmacologia
Nitroprussiato/farmacologia
Oxidiazóis/farmacologia
Estresse Oxidativo/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
Carbonilação Proteica/efeitos dos fármacos
Ratos Endogâmicos SHR
Ratos Endogâmicos WKY
Receptor Tipo 1 de Angiotensina/metabolismo
S-Nitroso-N-Acetilpenicilamina/farmacologia
Superóxidos/metabolismo
Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
Quinases da Família src/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one); 0 (Flavonoids); 0 (Nitric Oxide Donors); 0 (Oxadiazoles); 0 (Reactive Oxygen Species); 0 (Receptor, Angiotensin, Type 1); 0 (Thiobarbituric Acid Reactive Substances); 11062-77-4 (Superoxides); 169D1260KM (Nitroprusside); 31356-94-2 (8-bromocyclic GMP); 31C4KY9ESH (Nitric Oxide); 79032-48-7 (S-Nitroso-N-Acetylpenicillamine); 9007-49-2 (DNA); EC 1.6.3.- (NADPH Oxidases); EC 2.7.10.2 (src-Family Kinases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179301



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