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  1 / 3140 MEDLINE  
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[PMID]:28843869
[Au] Autor:Naik R; Valentine H; Hall A; Mathews WB; Harris JC; Carter CS; Dannals RF; Wong DF; Horti AG
[Ad] Endereço:Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore 21287, USA.
[Ti] Título:Development of a radioligand for imaging V vasopressin receptors with PET.
[So] Source:Eur J Med Chem;139:644-656, 2017 Oct 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of vasopressin receptor V ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1H-indol-3-yl)-3-methoxyphenyl) ((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with C for PET studies. [ CH ](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (∼2% ID/g tissue) and specifically (30-34%) labeled V receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [ CH ](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V receptor.
[Mh] Termos MeSH primário: Compostos Bicíclicos com Pontes/farmacologia
Sondas Moleculares/farmacologia
Tomografia por Emissão de Pósitrons
Receptores de Vasopressinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Compostos Bicíclicos com Pontes/síntese química
Compostos Bicíclicos com Pontes/química
Isótopos de Carbono
Relação Dose-Resposta a Droga
Ligantes
Camundongos
Sondas Moleculares/síntese química
Sondas Moleculares/química
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds); 0 (Carbon Isotopes); 0 (Ligands); 0 (Molecular Probes); 0 (Receptors, Vasopressin)
[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:170828
[St] Status:MEDLINE


  2 / 3140 MEDLINE  
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[PMID]:28767678
[Au] Autor:Janovick JA; Spicer TP; Bannister TD; Scampavia L; Conn PM
[Ad] Endereço:Departments of Internal Medicine and Cell Biology/Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, United States of America.
[Ti] Título:Pharmacoperone rescue of vasopressin 2 receptor mutants reveals unexpected constitutive activity and coupling bias.
[So] Source:PLoS One;12(8):e0181830, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pharmacoperones are small molecules that diffuse into cells and rescue misfolded, mistrafficked protein mutants, restoring their function. These substances act with high target specificity, serving as templates to fold (or refold) receptors, enzymes, ion channels or other proteins and enable them to pass the scrutiny of the cellular quality control system ("rescue"). In the present study we demonstrate that a rescued mutant (L83Q) of the vasopressin type 2 receptor (V2R), shows a strong bias for Gs coupling unlike the WT V2 receptor, which couples to both Gs and Gq/11. Failure of the mutant to couple to Gq/11 was not due to a limiting quantity of G-proteins since other Gq/11-coupled receptors (WT V2R, histamine receptor and muscarinic receptor) responded appropriately to their ligands. Transfection with DNA encoding Gq enabled the V2 receptor mutant to couple to this G protein, but only modestly compared with the WT receptor. Fourteen V2R mutant pharmacoperones, of multiple chemical classes, obtained from a high throughput screen of a 660,000 structure library, and one V2R peptidomimetic antagonist rescues L83Q. The rescued mutant shows similar bias with all pharmacoperones identified, suggesting that the bias is intrinsic to the mutant protein's structure, rather than due to the chemical class of the pharmacoperone. In the case of V2R mutant Y128S, rescue with a pharmacoperone revealed constitutive activity, also with bias for Gs, although both IP and cAMP were produced in response to agonist. These results suggest that particular rescued receptor mutants show functional characteristics that differ from the WT receptor; a finding that may be important to consider as pharmacoperones are developed as therapeutic agents.
[Mh] Termos MeSH primário: Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo
Morfolinas/farmacologia
Mutação
Receptores de Vasopressinas/genética
Compostos de Espiro/farmacologia
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Hormônios Antidiuréticos/química
Antagonistas de Receptores de Hormônios Antidiuréticos/farmacologia
AMP Cíclico/metabolismo
Células HeLa
Ensaios de Triagem em Larga Escala
Seres Humanos
Modelos Moleculares
Morfolinas/química
Receptores de Vasopressinas/química
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
Compostos de Espiro/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Morpholines); 0 (Receptors, Vasopressin); 0 (Small Molecule Libraries); 0 (Spiro Compounds); AJS8S3P31H (satavaptan); E0399OZS9N (Cyclic AMP); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gq-G11)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181830


  3 / 3140 MEDLINE  
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[PMID]:28714397
[Au] Autor:Golembiewska E; Machowska A; Stenvinkel P; Lindholm B
[Ad] Endereço:Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Al. Powstancow Wielkopolskich 72, 70-111 Szczecin. Poland.
[Ti] Título:Prognostic Value of Copeptin in Chronic Kidney Disease: From General Population to End-Stage Renal Disease.
[So] Source:Curr Protein Pept Sci;18(12):1232-1243, 2017.
[Is] ISSN:1875-5550
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is released in response to osmotic and non-osmotic stimuli and plays a key role in many physiologic and pathologic processes. The main function of AVP is the control of fluid homeostasis by inducing water conservation by the kidney, but it also stimulates arteriolar vasoconstriction and the release of adrenocorticotropic hormone (ACTH). These actions are mediated by different AVP receptors located on various target cells. Produced in hypothalamus from a larger precursor, pre-proAVP, AVP is produced in equimolar amounts to copeptin, a glycopeptide with yet unknown biologic function. Copeptin remains stable in plasma and its circulating concentrations correlate directly with those of AVP. Because AVP is unstable in isolated plasma or serum and its half-life is short, copeptin has become an easily measured surrogate marker reflecting vasopressin concentration. Recently, associations between high circulating copeptin and decline in glomerular filtration rate as well as greater risk of new-onset chronic kidney disease (CKD) have been reported. In addition, copeptin has been shown to be associated with increased risk of complications such as myocardial infarction, heart failure, diabetes mellitus and metabolic syndrome. In this brief review, studies on the prognostic value of copeptin measurement in the general population and in CKD are presented and discussed.
[Mh] Termos MeSH primário: Arginina Vasopressina/genética
Glicopeptídeos/genética
Hipotálamo/metabolismo
Falência Renal Crônica/diagnóstico
[Mh] Termos MeSH secundário: Hormônio Adrenocorticotrópico/sangue
Hormônio Adrenocorticotrópico/genética
Arginina Vasopressina/sangue
Biomarcadores/sangue
Progressão da Doença
Feminino
Regulação da Expressão Gênica
Taxa de Filtração Glomerular
Glicopeptídeos/sangue
Seres Humanos
Falência Renal Crônica/sangue
Falência Renal Crônica/genética
Falência Renal Crônica/patologia
Masculino
Prognóstico
Receptores de Vasopressinas/sangue
Receptores de Vasopressinas/genética
Fatores Sexuais
Transdução de Sinais
Vasopressinas/sangue
Vasopressinas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biomarkers); 0 (Glycopeptides); 0 (Receptors, Vasopressin); 0 (copeptins); 0 (proAVP hormone); 11000-17-2 (Vasopressins); 113-79-1 (Arginine Vasopressin); 9002-60-2 (Adrenocorticotropic Hormone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.2174/1389203718666170717095301


  4 / 3140 MEDLINE  
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[PMID]:28688111
[Au] Autor:Nakamura K; Velho G; Bouby N
[Ad] Endereço:Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
[Ti] Título:Vasopressin and metabolic disorders: translation from experimental models to clinical use.
[So] Source:J Intern Med;282(4):298-309, 2017 Oct.
[Is] ISSN:1365-2796
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Vasopressin has many physiological actions in addition to its well-defined role in the control of fluid homeostasis and urine concentration. An increasing body of evidence suggests that the vasopressin-hydration axis plays a role in glucose homeostasis. This review summarizes the knowledge accumulated over the last decades about the influence of vasopressin in the short-term regulation of glycaemia. It describes the possible role of this hormone through activation of V1a and V1b receptors on liver and pancreas functions and on the hypothalamic-pituitary-adrenal axis. Moreover, we report recent in vivo studies demonstrating the role of vasopressin in the long-term regulation of glycaemia. Indeed, V1a- or double-V1aV1b-receptor knockout mice display significant changes in the glucose and lipid metabolism. In rats, sustained high V1aR activation increases basal glycaemia and aggravates glucose intolerance in obese rats. Finally, the translation from animal findings to human was evidenced by epidemiological and genetic studies that showed that high vasopressin level is a risk factor for hyperglycaemia, metabolic disorders and diabetes.
[Mh] Termos MeSH primário: Doenças Metabólicas/fisiopatologia
Vasopressinas/fisiologia
[Mh] Termos MeSH secundário: Animais
Glicemia/fisiologia
Glucose/metabolismo
Glicopeptídeos/sangue
Glicopeptídeos/fisiologia
Homeostase/fisiologia
Seres Humanos
Obesidade/fisiopatologia
Ratos
Receptores de Vasopressinas/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Glycopeptides); 0 (Receptors, Vasopressin); 0 (copeptins); 11000-17-2 (Vasopressins); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1111/joim.12649


  5 / 3140 MEDLINE  
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[PMID]:28649750
[Au] Autor:Bankir L; Bichet DG; Morgenthaler NG
[Ad] Endereço:Centre de Recherche des Cordeliers, INSERM Unit 1138, 75006, Paris, France.
[Ti] Título:Vasopressin: physiology, assessment and osmosensation.
[So] Source:J Intern Med;282(4):284-297, 2017 Oct.
[Is] ISSN:1365-2796
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Vasopressin (AVP) plays a major role in the regulation of water and sodium homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. AVP secretion is stimulated by a rise in plasma osmolality, a decline in blood volume or stress. V1a receptors are expressed in vascular smooth muscle cells, but the role of vasopressin in blood pressure regulation is still a matter of debate. AVP may also play a role in some metabolic pathways, including gluconeogenesis, through its action on V1a receptors expressed in the liver. It is now understood that thirst and arginine vasopressin (AVP) release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. AVP measurement is time-consuming, and AVP level in the blood in the physiological range is often below the detection limit of the assays. Recently, an immunoassay has been developed for the measurement of copeptin, a fragment of the pre-provasopressin molecule that is easier to measure. It has been shown to be a good surrogate marker of AVP.
[Mh] Termos MeSH primário: Osmorregulação/fisiologia
Vasopressinas/fisiologia
[Mh] Termos MeSH secundário: Animais
Ingestão de Líquidos/fisiologia
Ingestão de Alimentos/fisiologia
Glicopeptídeos/sangue
Glicopeptídeos/fisiologia
Seres Humanos
Ilhotas Pancreáticas/fisiologia
Rim/fisiologia
Fígado/fisiologia
Receptores de Vasopressinas/fisiologia
Sede/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Glycopeptides); 0 (Receptors, Vasopressin); 0 (copeptins); 11000-17-2 (Vasopressins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE
[do] DOI:10.1111/joim.12645


  6 / 3140 MEDLINE  
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[PMID]:28475329
[Au] Autor:Tabata H; Yoneda T; Oshitari T; Takahashi H; Natsugari H
[Ad] Endereço:Faculty of Pharma Sciences, Teikyo University , 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
[Ti] Título:Tolvaptan-Type Vasopressin Receptor Ligands: Important Role of Axial Chirality in the Active Form.
[So] Source:J Med Chem;60(10):4503-4509, 2017 May 25.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The anti and syn isomers of tolvaptan-type compounds, N-benzoyl-5-hydroxy-1-benzazepines (5a-c), were prepared in a stereocontrolled manner by biasing the conformation with a methyl group at C9 and C6, respectively, and the enantiomeric forms were separated. Examination of the affinity at the human vasopressin receptors revealed that the axial chirality (aS) plays a more important role than the central chirality at C5 in receptor recognition, and the most preferable form was shown to be (E,aS,5S).
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos/química
Antagonistas de Receptores de Hormônios Antidiuréticos/farmacologia
Benzazepinas/química
Benzazepinas/farmacologia
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Seres Humanos
Ligantes
Modelos Moleculares
Receptores de Vasopressinas/química
Receptores de Vasopressinas/metabolismo
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 0 (Ligands); 0 (Receptors, Vasopressin); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170506
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00422


  7 / 3140 MEDLINE  
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[PMID]:28432473
[Au] Autor:Vishram-Nielsen JK; Gustafsson F
[Ad] Endereço:Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
[Ti] Título:Vasopressin and Vasopressin Antagonists in Heart Failure.
[So] Source:Handb Exp Pharmacol;243:307-328, 2017.
[Is] ISSN:0171-2004
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Despite the introduction of multiple new pharmacological agents over the past three decades in the field of heart failure (HF), overall prognosis remains poor. Hyponatremia is prevalent in HF patients and has been suggested as a contributor to poor response to standard therapy. Elevated levels of arginine vasopressin (AVP), a peptide hormone produced in the hypothalamus, play a role in development of hyponatremia, and AVP and its surrogate, copeptin, are related to changes in osmolality, hemodynamics, neuro-hormones as well as in overall outcome in HF patients. Of current pharmacological interest are the selective and non-selective vasopressin receptor antagonists (VRAs), which inhibit vasoconstriction and cardiac remodeling mediated by the V receptors in smooth blood vessels, and water retention (increased urine osmolality and decreased water excretion) by increasing aquaporin-2 water channels mediated by the V receptors in the renal collecting tubules. The optimal use of VRAs is yet to be determined, especially in patients with congestive HF. Although long-term effects on improvement in mortality have not been shown in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, the only long-term outcome trial to date, many short-term studies indicate beneficial aquaretic- and hemodynamic-effects of the VRAs. In contrast to loop diuretics, these new agents tend to increase urine flow and the excretion of electrolyte-free water (so-called aquaresis) in patients with HF, without substantial changes in sodium or potassium excretion. This chapter reviews the role of AVP and copeptin in HF, and the treatment potential of VRAs in HF.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos/uso terapêutico
Insuficiência Cardíaca/tratamento farmacológico
[Mh] Termos MeSH secundário: Arginina Vasopressina/metabolismo
Benzazepinas/uso terapêutico
Glicopeptídeos/metabolismo
Insuficiência Cardíaca/metabolismo
Hemodinâmica
Seres Humanos
Hiponatremia/metabolismo
Receptores de Vasopressinas/metabolismo
Vasopressinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 0 (Glycopeptides); 0 (Receptors, Vasopressin); 0 (copeptins); 11000-17-2 (Vasopressins); 113-79-1 (Arginine Vasopressin); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170423
[St] Status:MEDLINE
[do] DOI:10.1007/164_2017_28


  8 / 3140 MEDLINE  
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[PMID]:28419717
[Au] Autor:Martínez-Archundia M; Colín-Astudillo B; Moreno-Vargas LM; Ramírez-Galicia G; Garduño-Juárez R; Deeb O; Contreras-Romo MC; Quintanar-Stephano A; Abarca-Rojano E; Correa-Basurto J
[Ad] Endereço:Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina-Instituto Politécnico Nacional, México City, Mexico.
[Ti] Título:Ligand recognition properties of the vasopressin V2 receptor studied under QSAR and molecular modeling strategies.
[So] Source:Chem Biol Drug Des;90(5):840-853, 2017 Nov.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The design of new drugs that target vasopressin 2 receptor (V2R) is of vital importance to develop new therapeutic alternatives to treat diseases such as heart failure, polycystic kidney disease. To get structural insights related to V2R-ligand recognition, we have used a combined approach of docking, molecular dynamics simulations (MD) and quantitative structure-activity relationship (QSAR) to elucidate the detailed interaction of the V2R with 119 of its antagonists. The three-dimensional model of V2R was built by threading methods refining its structure through MD simulations upon which the 119 ligands were subjected to docking studies. The theoretical results show that binding recognition of these ligands on V2R is diverse, but the main pharmacophore (electronic and π-π interactions) is maintained; thus, this information was validated under QSAR results. QSAR studies were performed using MLR analysis followed by ANN analysis to increase the model quality. The final equation was developed by choosing the optimal combination of descriptors after removing the outliers. The applicability domains of the constructed QSAR models were defined using the leverage and standardization approaches. The results suggest that the proposed QSAR models can reliably predict the reproductive toxicity potential of diverse chemicals, and they can be useful tools for screening new chemicals for safety assessment.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos/química
Antagonistas de Receptores de Hormônios Antidiuréticos/farmacologia
Receptores de Vasopressinas/metabolismo
[Mh] Termos MeSH secundário: Desenho de Drogas
Seres Humanos
Ligantes
Simulação de Dinâmica Molecular
Relação Quantitativa Estrutura-Atividade
Receptores de Vasopressinas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Ligands); 0 (Receptors, Vasopressin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.13005


  9 / 3140 MEDLINE  
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[PMID]:28418999
[Au] Autor:Masuki S; Morikawa M; Nose H
[Ad] Endereço:1Department of Sports Medical Sciences, Graduate School of Medicine, 2Institute for Biomedical Sciences, Shinshu University; and 3Jukunen Taiikudaigaku Research Center, Matsumoto, Japan.
[Ti] Título:Interval Walking Training Can Increase Physical Fitness in Middle-Aged and Older People.
[So] Source:Exerc Sport Sci Rev;45(3):154-162, 2017 Jul.
[Is] ISSN:1538-3008
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:No long-term exercise training regimen with high adherence and effectiveness for middle-aged and older individuals is currently broadly available in the field. To address this problem, we developed an exercise training system comprising interval walking training and an information technology network that requires only minimal staff support. We hypothesized that our training system could increase physical fitness in older people.
[Mh] Termos MeSH primário: Envelhecimento/fisiologia
Condicionamento Físico Humano/métodos
Aptidão Física/fisiologia
Caminhada/fisiologia
[Mh] Termos MeSH secundário: Idoso
Animais
Artroplastia de Quadril/reabilitação
Calorimetria/métodos
Suplementos Nutricionais
Seres Humanos
Meia-Idade
Receptores de Vasopressinas/fisiologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Vasopressin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1249/JES.0000000000000113


  10 / 3140 MEDLINE  
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[PMID]:28381458
[Au] Autor:Cheung PW; Ueberdiek L; Day J; Bouley R; Brown D
[Ad] Endereço:Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
[Ti] Título:Protein phosphatase 2C is responsible for VP-induced dephosphorylation of AQP2 serine 261.
[So] Source:Am J Physiol Renal Physiol;313(2):F404-F413, 2017 Aug 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aquaporin 2 (AQP2) trafficking is regulated by phosphorylation and dephosphorylation of serine residues in the AQP2 COOH terminus. Vasopressin (VP) binding to its receptor (V2R) leads to a cascade of events that result in phosphorylation of serine 256 (S256), S264, and S269, but dephosphorylation of S261. To identify which phosphatase is responsible for VP-induced S261 dephosphorylation, we pretreated cells with different phosphatase inhibitors before VP stimulation. Sanguinarine, a specific protein phosphatase (PP) 2C inhibitor, but not inhibitors of PP1, PP2A (okadaic acid), or PP2B (cyclosporine), abolished VP-induced S261 dephosphorylation. However, sanguinarine and VP significantly increased phosphorylation of ERK, a kinase that can phosphorylate S261; inhibition of ERK by PD98059 partially decreased baseline S261 phosphorylation. These data support a role of ERK in S261 phosphorylation but suggest that, upon VP treatment, increased phosphatase activity overcomes the increase in ERK activity, resulting in overall dephosphorylation of S261. We also found that sanguinarine abolished VP-induced S261 dephosphorylation in cells expressing mutated AQP2 S256A, suggesting that the phosphorylation state of S261 is independent of S256. Sanguinarine alone did not induce AQP2 membrane trafficking, nor did it inhibit VP-induced AQP2 membrane accumulation in cells and kidney tissues, suggesting that S261 does not play an observable role in acute AQP2 membrane accumulation. In conclusion, PP2C activity is required for S261 AQP2 dephosphorylation upon VP stimulation, which occurs independently of S256 phosphorylation. Understanding the pathways involved in modulating PP2C will help elucidate the role of S261 in cellular events involving AQP2.
[Mh] Termos MeSH primário: Aquaporina 2/metabolismo
Rim/efeitos dos fármacos
Vasopressinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Aquaporina 2/genética
Inibidores Enzimáticos/farmacologia
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Técnicas In Vitro
Rim/enzimologia
Células LLC-PK1
Mutação
Fosforilação
Proteína Fosfatase 2C/antagonistas & inibidores
Proteína Fosfatase 2C/metabolismo
Transporte Proteico
Ratos Sprague-Dawley
Receptores de Vasopressinas/agonistas
Receptores de Vasopressinas/metabolismo
Serina
Transdução de Sinais/efeitos dos fármacos
Suínos
Transfecção
Vasopressinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aqp2 protein, rat); 0 (Aquaporin 2); 0 (Enzyme Inhibitors); 0 (Receptors, Vasopressin); 0 (V2 vasopressin receptor, rat); 11000-17-2 (Vasopressins); 452VLY9402 (Serine); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.1.3.16 (Protein Phosphatase 2C)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170407
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00004.2017



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