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[PMID]:28449948
[Au] Autor:Lutz SZ; Ullrich A; Häring HU; Ullrich S; Gerst F
[Ad] Endereço:German Center for Diabetes Research (DZD e.V.), Germany; Institute for Diabetes Research and Metabolic Diseases IDM of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Germany; University Hospital Tübingen, Internal Medicine IV, Endocrinology, Diabetology, Angiology, Nephrol
[Ti] Título:Sunitinib specifically augments glucose-induced insulin secretion.
[So] Source:Cell Signal;36:91-97, 2017 Aug.
[Is] ISSN:1873-3913
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting ß-cells. Regulation of insulin secretion, of cellular cAMP levels and activation of signalling pathways were examined upon exposure of rat insulinoma INS-1E cells to sunitinib under specific stimulatory and inhibitory conditions. Secreted insulin and cellular cAMP levels were measured using RIA and ELISA, respectively. Protein phosphorylations were examined on western blots. Sunitinib enhanced glucose-induced insulin secretion (GIIS) concentration-dependently, reaching a maximal stimulation at 2µM. Sunitinib further augmented insulin secretion in the presence of elevated cAMP levels and the FFAR1 agonists. Adrenaline and the PKA inhibitor H89 counteracted the stimulatory effect of sunitinib on secretion. However, sunitinib altered neither the cellular levels of cAMP nor the phosphorylation of PKA. Sunitinib did not reduce IGF-1-induced phosphorylation of AKT/PKB and ERK1/2. In conclusion, these results suggest that sunitinib stimulates GIIS by a direct effect on ß-cells, which may contribute to the glucose-lowering action of the tyrosine kinase inhibitor in humans.
[Mh] Termos MeSH primário: Glucose/farmacologia
Indóis/farmacologia
Insulina/secreção
Pirróis/farmacologia
[Mh] Termos MeSH secundário: Compostos de Anilina
Animais
Linhagem Celular
Colforsina/farmacologia
AMP Cíclico/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Isoquinolinas/farmacologia
Fenilpropionatos
Fosforilação/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
Ratos
Transdução de Sinais/efeitos dos fármacos
Sulfonamidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (H-89 dihydrochloride hydrate); 0 (Indoles); 0 (Insulin); 0 (Isoquinolines); 0 (Phenylpropionates); 0 (Protein Kinase Inhibitors); 0 (Pyrroles); 0 (Sulfonamides); 0 (TUG-469); 1F7A44V6OU (Colforsin); 67763-96-6 (Insulin-Like Growth Factor I); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); IY9XDZ35W2 (Glucose); V99T50803M (sunitinib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


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[PMID]:29254302
[Au] Autor:Wang Q; Wang J; Gao D; Li J
[Ad] Endereço:Tumor Center, The First Hospital of Jilin University, Changchun, Jilin, China.
[Ti] Título:Inhibition of PAR2 and TRPA1 signals alleviates neuropathic pain evoked by chemotherapeutic bortezomib.
[So] Source:J Biol Regul Homeost Agents;31(4):977-983, 2017 Oct-Dec.
[Is] ISSN:0393-974X
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:Bortezomib (BTZ) is generally used as a chemotherapeutic agent for the treatment of multiple myeloma; however, one of the significant limiting complications of BTZ is painful peripheral neuropathy observed during BTZ therapy. There is a lack of drugs which can prevent and/or treat the painful symptoms induced by BTZ, as the underlying molecular mechanism leading to neuropathic pain remains largely unclear. In the present study, we examined engagement of proteinase-activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) in neuropathic pain induced by BTZ in rats. Our results demonstrated that systemic injection of BTZ increased mechanical pain and cold sensitivity as compared with control animals (P less than 0.05 vs control rats). Our data further showed that blocking respective PAR2 and TRPA1 attenuated mechanical pain and cold sensitivity observed in control rats and BTZ rats (P less than 0.05 vs vehicle control). Notably, the attenuating effect of blocking PAR2 and TRPA1 on mechanical pain and cold sensitivity was significantly less in BTZ rats than that in control rats. In addition, protein expression of PAR2 and TRPA1 was upregulated in the lumbar dorsal root ganglion of BTZ rats, and inhibition of PAR2 decreased the levels of TRPA1 and attenuated its downstream pathways (namely, PKCÉ› and PKA). Overall, we revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ and that blocking PAR2 and TRPA1 in sensory nerves is beneficial to improve neuropathic pain during BTZ intervention.
[Mh] Termos MeSH primário: Analgésicos/farmacologia
Antineoplásicos/efeitos adversos
Bortezomib/efeitos adversos
Neuralgia/prevenção & controle
Oligopeptídeos/farmacologia
Receptor PAR-2/antagonistas & inibidores
Canal de Cátion TRPA1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Proteínas Quinases Dependentes de AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Gânglios Espinais/efeitos dos fármacos
Gânglios Espinais/metabolismo
Gânglios Espinais/fisiopatologia
Regulação da Expressão Gênica
Hiperalgesia/induzido quimicamente
Hiperalgesia/genética
Hiperalgesia/fisiopatologia
Hiperalgesia/prevenção & controle
Masculino
Neuralgia/induzido quimicamente
Neuralgia/genética
Neuralgia/fisiopatologia
Proteína Quinase C-épsilon/genética
Proteína Quinase C-épsilon/metabolismo
Ratos
Ratos Sprague-Dawley
Receptor PAR-2/genética
Receptor PAR-2/metabolismo
Transdução de Sinais
Canal de Cátion TRPA1/genética
Canal de Cátion TRPA1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Antineoplastic Agents); 0 (H-Phe-Ser-Leu-Leu-Arg-Tyr-NH2); 0 (Oligopeptides); 0 (Receptor, PAR-2); 0 (TRPA1 Cation Channel); 0 (Trpa1 protein, rat); 69G8BD63PP (Bortezomib); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.13 (Protein Kinase C-epsilon)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171220
[St] Status:MEDLINE


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[PMID]:29258870
[Au] Autor:Heimfarth L; Delgado J; Mingori MR; Moresco KS; Pureur RP; Gelain DP; Moreira JCF
[Ad] Endereço:Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil. Electronic address: luahei@yahoo.com.br.
[Ti] Título:Delayed neurochemical effects of prenatal exposure to MeHg in the cerebellum of developing rats.
[So] Source:Toxicol Lett;284:161-169, 2018 Mar 01.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Human fetuses and neonates are particularly vulnerable to methylmercury (MeHg)-induced brain damage and are sensitive even to low exposure levels. Previous work of our group evidence that prenatal exposure to MeHg causes cognitive and behavioral alterations and disrupt hippocampus signaling. The current study aimed to investigate the effect of gestational exposure of rats to MeHg at low doses (1 or 2 mg/kg) on parameters of redox imbalance and key signaling pathways in the cerebellum of their offspring. Pregnant females received MeHg (treated group) or 0.9% saline water (control group) by gavage in alternated days from gestational day 5 (GD5) until parturition and analyzes were proceed in the cerebellum of 30-day-old pups. We found increased lipid peroxidation and protein carbonylation levels as well as decreased SH content in pups prenatally exposed to 2 mg/kg MeHg. In addition, misregulated SOD/catalase activities supported imbalanced redox equilibrium. We found decreased GSK3ß(Ser9) phosphorylation, suggesting activation of this enzyme and dephosphorylation/inhibition of ERK1/2 and JNK pathways. Increased PKAα catalytic subunit could be upstream of hyperphosphorylated c-Raf(Ser259) and downregulated MAPK pathway. In addition, we found raised levels of the Ca -dependent protein phosphatase 2 B (PP2B). We also found preserved immunohistochemical staining for both glial fibrillary acidic protein (GFAP) and NeuN in MeHg-exposed pups. Western blot analysis showed unaltered levels of BAX/BCL-XL, BAD/BCL-2 and active caspase 3. Together, these findings support absence of reactive astrocytes, neuronal damage and apoptotic cell death in the cerebellum of MeHg treated pups. The present study provides evidence that prenatal exposure to MeHg leads to later redox imbalance and disrupted signaling mechanisms in the cerebellum of 30-day-old pups potentially predisposing them to long-lasting neurological impairments in CNS.
[Mh] Termos MeSH primário: Cerebelo/efeitos dos fármacos
Poluentes Ambientais/toxicidade
Compostos de Metilmercúrio/toxicidade
Neurônios/efeitos dos fármacos
Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
Efeitos Tardios da Exposição Pré-Natal/metabolismo
[Mh] Termos MeSH secundário: Animais
Cerebelo/crescimento & desenvolvimento
Cerebelo/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Relação Dose-Resposta a Droga
Feminino
Glicogênio Sintase Quinase 3 beta/metabolismo
Peroxidação de Lipídeos/efeitos dos fármacos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Masculino
Neurônios/metabolismo
Oxirredução
Gravidez
Carbonilação Proteica/efeitos dos fármacos
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Environmental Pollutants); 0 (Methylmercury Compounds); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.1 (Gsk3b protein, rat); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE


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[PMID]:29317208
[Au] Autor:Xiao XH; Qi XY; Wang YD; Ran L; Yang J; Zhang HL; Xu CX; Wen GB; Liu JH
[Ad] Endereço:Department of Metabolism and Endocrinology, University of South China, Hengyang, 421001, Hunan Province, China.
[Ti] Título:Zinc alpha2 glycoprotein promotes browning in adipocytes.
[So] Source:Biochem Biophys Res Commun;496(2):287-293, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called "browning") would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.
[Mh] Termos MeSH primário: Adipócitos Marrons/metabolismo
Proteínas de Transporte/genética
Regulação da Expressão Gênica
Glicoproteínas/genética
Metabolismo dos Lipídeos/genética
[Mh] Termos MeSH secundário: Células 3T3-L1
Adipócitos Marrons/citologia
Adipócitos Marrons/efeitos dos fármacos
Animais
Proteínas Reguladoras de Apoptose/genética
Proteínas Reguladoras de Apoptose/metabolismo
Carbono-Carbono Ligases/genética
Carbono-Carbono Ligases/metabolismo
Carnitina O-Palmitoiltransferase/genética
Carnitina O-Palmitoiltransferase/metabolismo
Proteínas de Transporte/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Glicoproteínas/metabolismo
Imidazóis/farmacologia
Isoquinolinas/farmacologia
Lipase/genética
Lipase/metabolismo
Camundongos
Fator 2 Relacionado a NF-E2/genética
Fator 2 Relacionado a NF-E2/metabolismo
Fator 1 Nuclear Respiratório/genética
Fator 1 Nuclear Respiratório/metabolismo
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
Piridinas/farmacologia
Transdução de Sinais
Sulfonamidas/farmacologia
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Proteína Desacopladora 1/genética
Proteína Desacopladora 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AZGP1 protein, mouse); 0 (Apoptosis Regulatory Proteins); 0 (Carrier Proteins); 0 (Cidea protein, mouse); 0 (DNA-Binding Proteins); 0 (Glycoproteins); 0 (Imidazoles); 0 (Isoquinolines); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 0 (Nrf1 protein, mouse); 0 (Nuclear Respiratory Factor 1); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Ppargc1a protein, mouse); 0 (Prdm16 protein, mouse); 0 (Pyridines); 0 (Sulfonamides); 0 (Transcription Factors); 0 (Ucp1 protein, mouse); 0 (Uncoupling Protein 1); EC 2.3.1.21 (CPT1B protein, mouse); EC 2.3.1.21 (Carnitine O-Palmitoyltransferase); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.1.3 (Lipase); EC 3.1.1.3 (PNPLA2 protein, mouse); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.1.- (acyl-CoA carboxylase); M876330O56 (N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide); OU13V1EYWQ (SB 203580)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


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


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[PMID]:29225111
[Au] Autor:Xu X; Chen J; Hu L; Liang M; Wang X; Feng S; Shen J; Luan X
[Ad] Endereço:Department of Endocrinology, the First People's Hospital of Foshan, Foshan, Guangdong 52800, China; Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Endocrinology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510515, China.
[Ti] Título:Liraglutide regulates the viability of pancreatic α-cells and pancreatic ß-cells through cAMP-PKA signal pathway.
[So] Source:Life Sci;195:87-94, 2018 Feb 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: As a glucagon-like peptide-1 receptor agonist, liraglutide could effectively increase insulin secretion from pancreatic ß-cells and suppress glucagon secretion from pancreatic α-cells in the treatment of hyperglycemia in type 2 diabetes patients. However, the mechanisms for the different regulation of pancreatic α-cells and ß-cells are still unclear. In this study, we mainly explored the different effects of liraglutide on mouse pancreatic α-cell line and ß-cell line in vitro. MAIN METHODS: Herein, mouse pancreatic α-cell line, α-TC1-6, and mouse pancreatic ß-cell line, ß-TC-tet, were used to analyze the biological effects of liraglutide in different concentrations. Cell proliferation, cell apoptosis and cell secretion ability were detected in different groups. Besides, the level of miR-375 and cAMP-PKA signal pathway were further evaluated using qPCR and western blot. KEY FINDINGS: The results indicated that liraglutide could increase the level of miR-375 and cell apoptosis in pancreatic α-cells through inhibiting the cAMP-PKA signal pathway, but activate cAMP-PKA signal pathway in pancreatic ß-cells, and further lead to the down-regulation of miR-375 and improve cell viability. Therefore, the treatment with liraglutide could down-regulate the glucagon secretion ability of α-TC1-6 cells, and the insulin secretion ability of ß-TC-tet cells was enhanced with the liraglutide treatment in a dose-dependent manner. SIGNIFICANCE: In conclusion, we mainly found that liraglutide could regulate the viability of pancreatic α-cells and pancreatic ß-cells through inhibiting and activating cAMP-PKA signal pathway respectively. The better understanding of the mechanism could help us to develop more novel therapy methods for diabetes in the future.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/fisiologia
AMP Cíclico/fisiologia
Células Secretoras de Glucagon/efeitos dos fármacos
Hipoglicemiantes/farmacologia
Células Secretoras de Insulina/efeitos dos fármacos
Liraglutida/farmacologia
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Glucagon/secreção
Células Secretoras de Glucagon/secreção
Insulina/secreção
Células Secretoras de Insulina/secreção
Camundongos
MicroRNAs/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypoglycemic Agents); 0 (Insulin); 0 (MicroRNAs); 0 (Mirn375 microRNA, mouse); 839I73S42A (Liraglutide); 9007-92-5 (Glucagon); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


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[PMID]:28460125
[Au] Autor:Law NC; Donaubauer EM; Zeleznik AJ; Hunzicker-Dunn M
[Ad] Endereço:School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164.
[Ti] Título:How Protein Kinase A Activates Canonical Tyrosine Kinase Signaling Pathways To Promote Granulosa Cell Differentiation.
[So] Source:Endocrinology;158(7):2043-2051, 2017 07 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein kinase A (PKA) has recently been shown to mimic the actions of follicle-stimulating hormone (FSH) by activating signaling pathways that promote granulosa cell (GC) differentiation, such as phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). We sought to elucidate the mechanism by which PKA, a Ser/Thr kinase, intersected the PI3K/AKT and MAPK/ERK pathways that are canonically activated by receptor tyrosine kinases (RTKs). Our results show that for both of these pathways, the RTK is active in the absence of FSH yet signaling down the pathways to commence transcriptional responses requires FSH-stimulated PKA activation. For both pathways, PKA initiates signaling by regulating the activity of a protein phosphatase (PP). For the PI3K/AKT pathway, PKA activates the Ser/Thr PP1 complexed with the insulinlike growth factor 1 receptor (IGF-1R) and insulin receptor substrate 1 (IRS1) to dephosphorylate Ser residues on IRS1, authorizing phosphorylation of IRS1 by the IGF-1R to activate PI3K. Treatment of GCs with FSH and exogenous IGF-1 initiates synergistic IRS1 Tyr phosphorylation and resulting gene activation. The mechanism by which PKA activates PI3K is conserved in preovulatory GCs, MCF7 breast cancer cells, and FRTL thyroid cells. For the MAPK/ERK pathway, PKA promotes inactivation of the MAPK phosphatase (MKP) dual specificity phosphatase (DUSP) MKP3/DUSP6 to permit MEK-phosphorylated ERK to accumulate downstream of the epidermal growth factor receptor. Thus, for the two central signaling pathways that regulate gene expression in GCs, FSH via PKA intersects canonical RTK-regulated signaling by modulating the activity of PPs.
[Mh] Termos MeSH primário: Diferenciação Celular
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia
Células da Granulosa/fisiologia
Proteínas Tirosina Quinases/metabolismo
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/genética
Células Cultivadas
Proteínas Quinases Dependentes de AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Ativação Enzimática
Feminino
Seres Humanos
Proteínas Substratos do Receptor de Insulina/metabolismo
Sistema de Sinalização das MAP Quinases/genética
Células MCF-7
Fosforilação
Ratos
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (IRS1 protein, human); 0 (Insulin Receptor Substrate Proteins); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180203
[Lr] Data última revisão:
180203
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00163


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[PMID]:29232706
[Au] Autor:Guillory AN; Clayton RP; Prasai A; El Ayadi A; Herndon DN; Finnerty CC
[Ad] Endereço:Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America.
[Ti] Título:Biventricular differences in ß-adrenergic receptor signaling following burn injury.
[So] Source:PLoS One;12(12):e0189527, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Burn injury detrimentally affects the myocardium, primarily due to over-activation of ß-adrenergic receptors (ß-AR). Autopsy reports from our institution reveal that patients often suffer from right ventricle (RV) failure. Since burn injury affects ß-AR signaling in the left ventricle (LV), we proposed that ß-AR signaling may also be altered in the RV. A rodent model with a scald burn of 60% of the total body surface area was used to test this hypothesis. Ventricles were isolated 7 days post-burn. We examined the expression of ß-ARs via Western blotting and the mRNA expression of downstream signaling proteins via qRT-PCR. Cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity were measured in membrane and cytosolic fractions, respectively, using enzyme immunoassay kits. ß1-AR protein expression was significantly increased in the RV following burn injury compared to non-burned RV but not in the LV (p = 0.0022). In contrast, ß2-AR expression was unaltered among the groups while Gαi expression was significantly higher in the LV post-burn (p = 0.023). B-arrestin-1 and G-protein coupled receptor kinase-2 mRNA expression were significantly increased in the left ventricle post-burn (p = 0.001, p<0.0001, respectively). cAMP production and PKA activity were significantly lower in the LV post-burn (p = 0.0063, 0.0042, respectively). These data indicate that burn injury affects the ß-AR signaling pathway in the RV independently of the LV. Additionally, non-canonical ß-AR signaling may be activated in the RV as cAMP production and PKA activity were unchanged despite changes in ß1-AR protein expression.
[Mh] Termos MeSH primário: Ventrículos do Coração/metabolismo
Receptores Adrenérgicos beta/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
AMP Cíclico/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Masculino
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Adrenergic, beta); 67763-96-6 (Insulin-Like Growth Factor I); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189527


  9 / 15577 MEDLINE  
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[PMID]:29183753
[Au] Autor:Lee CH; Chu CS; Tsai HJ; Ke LY; Lee HC; Yeh JL; Chen CH; Wu BN
[Ad] Endereço:Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
[Ti] Título:Xanthine-derived KMUP-1 reverses glucotoxicity-activated Kv channels through the cAMP/PKA signaling pathway in rat pancreatic ß cells.
[So] Source:Chem Biol Interact;279:171-176, 2018 Jan 05.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Hyperglycemia-associated glucotoxicity induces ß-cell dysfunction and a reduction in insulin secretion. Voltage-dependent K (Kv) channels in pancreatic ß-cells play a key role in glucose-dependent insulin secretion. KMUP-1, a xanthine derivative, has been demonstrated to modulate Kv channel activity in smooth muscles; however, the role of KMUP-1 in glucotoxicity-activated Kv channels in pancreatic ß-cells remains unclear. In this study we examined the mechanisms by which KMUP-1 could inhibit high glucose (25 mM) activated Kv currents (IKv) in pancreatic ß-cells. Pancreatic ß-cells were isolated from Wistar rats and IKv was monitored by perforated patch-clamp recording. The peak IKv in high glucose-treated ß-cells was ∼1.4-fold greater than for normal glucose (5.6 mM). KMUP-1 (1, 10, 30 µM) prevented high glucose-stimulated IKv in a concentration-dependent manner. Reduction of high glucose-activated IKv was also found for protein kinase A (PKA) activator 8-Br-cAMP (100 µM). Additionally, KMUP-1 (30 µM) current inhibition was reversed by the PKA inhibitor H-89 (1 µM). Otherwise, pretreatment with the PKC activator or inhibitor had no effect on IKv in high glucose exposure. In conclusion, glucotoxicity-diminished insulin secretion was due to IKv activation. KMUP-1 attenuated high glucose-stimulated IKv via the PKA but not the PKC signaling pathway. This finding provides evidence that KMUP-1 might be a promising agent for treating hyperglycemia-induced insulin resistance.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
AMP Cíclico/metabolismo
Glucose/toxicidade
Células Secretoras de Insulina/efeitos dos fármacos
Piperidinas/farmacologia
Canais de Potássio/metabolismo
Xantinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Insulina/secreção
Células Secretoras de Insulina/metabolismo
Ratos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (Piperidines); 0 (Potassium Channels); 0 (Xanthines); 1X0H7WEC5D (KMUP 1); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180103
[Lr] Data última revisão:
180103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE


  10 / 15577 MEDLINE  
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[PMID]:28468835
[Au] Autor:Hovsepian J; Defenouillère Q; Albanèse V; Váchová L; Garcia C; Palková Z; Léon S
[Ad] Endereço:Institut Jacques Monod, UMR 7592 Centre National de la Recherche Scientifique/Université Paris-Diderot, Sorbonne Paris Cité, 75013 Paris, France.
[Ti] Título:Multilevel regulation of an α-arrestin by glucose depletion controls hexose transporter endocytosis.
[So] Source:J Cell Biol;216(6):1811-1831, 2017 Jun 05.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nutrient availability controls the landscape of nutrient transporters present at the plasma membrane, notably by regulating their ubiquitylation and subsequent endocytosis. In yeast, this involves the Nedd4 ubiquitin ligase Rsp5 and arrestin-related trafficking adaptors (ARTs). ARTs are targeted by signaling pathways and warrant that cargo ubiquitylation and endocytosis appropriately respond to nutritional inputs. Here, we show that glucose deprivation regulates the ART protein Csr2/Art8 at multiple levels to trigger high-affinity glucose transporter endocytosis. Csr2 is transcriptionally induced in these conditions through the AMPK orthologue Snf1 and downstream transcriptional repressors. Upon synthesis, Csr2 becomes activated by ubiquitylation. In contrast, glucose replenishment induces transcriptional shutdown and switches Csr2 to an inactive, deubiquitylated form. This glucose-induced deubiquitylation of Csr2 correlates with its phospho-dependent association with 14-3-3 proteins and involves protein kinase A. Thus, two glucose signaling pathways converge onto Csr2 to regulate hexose transporter endocytosis by glucose availability. These data illustrate novel mechanisms by which nutrients modulate ART activity and endocytosis.
[Mh] Termos MeSH primário: Arrestina/metabolismo
Endocitose
Glucose/deficiência
Proteínas de Transporte de Monossacarídeos/metabolismo
Proteínas Nucleares/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Proteínas 14-3-3/metabolismo
Arrestina/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Regulação Fúngica da Expressão Gênica
Proteínas de Transporte de Monossacarídeos/genética
Mutação
Proteínas Nucleares/genética
Proteína Fosfatase 1/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Repressoras/metabolismo
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
Fatores de Tempo
Transcrição Genética
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (14-3-3 Proteins); 0 (Arrestin); 0 (BMH1 protein, S cerevisiae); 0 (BMH2 protein, S cerevisiae); 0 (Csr2 protein, S cerevisiae); 0 (HXT7 protein, S cerevisiae); 0 (Hxt6 protein, S cerevisiae); 0 (MIG1 protein, S cerevisiae); 0 (Mig2 protein, S cerevisiae); 0 (Monosaccharide Transport Proteins); 0 (Nuclear Proteins); 0 (Repressor Proteins); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.1.- (SNF1-related protein kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.3.16 (Protein Phosphatase 1); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201610094



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