Base de dados : MEDLINE Pesquisa : D12.776.157.530.450.074.750.750.750 [Categoria DeCS] Referências encontradas : 146 [refinar] Mostrando: 1 .. 10   no formato [Detalhado]

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[PMID]: 27784684 [Au] Autor: Werner A; Patti M; Zinad HS; Fearn A; Laude A; Forster I [Ad] Endereço: Institute for Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom; andreas.werner@ncl.ac.uk. [Ti] Título: Molecular determinants of transport function in zebrafish Slc34a Na-phosphate transporters. [So] Source: Am J Physiol Regul Integr Comp Physiol;311(6):R1213-R1222, 2016 Dec 01. [Is] ISSN: 1522-1490 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The epithelial Na -coupled phosphate cotransporter family Slc34a (NaPi-II) is well conserved in vertebrates and plays an essential role in maintaining whole body levels of inorganic phosphate (P ). A three-dimensional model of the transport protein has recently been proposed with defined substrate coordination sites. Zebrafish express two NaPi-II isoforms with high sequence identity but a 10-fold different apparent K for P ([Formula: see text]). We took advantage of the two zebrafish isoforms to investigate the contribution of specific amino acids to P coordination and transport. Mutations were introduced to gradually transform the low-affinity isoform into a high-affinity transporter. The constructs were expressed in Xenopus laevis oocytes and functionally characterized. Becaue the cotransport of P and Na involves multiple steps that could all influence [Formula: see text], we performed a detailed functional analysis to characterize the impact of the mutations on particular steps of the transport cycle. We used varying concentrations of the substrates P and its slightly larger analog, arsenate, as well as the cosubstrate, Na Moreover, electrogenic kinetics were performed to assess intramolecular movements of the transporter. All of the mutations were found to affect multiple transport steps, which suggested that the altered amino acids induced subtle structural changes rather than coordinating P directly. The likely positions of the critical residues were mapped to the model of human Slc34a, and their localization in relation to the proposed substrate binding pockets concurs well with the observed functional data. [Mh] Termos MeSH primário: Aminoácidos/química Fosfatos/química Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/química Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/ultraestrutura Sódio/química Proteínas de Peixe-Zebra/química [Mh] Termos MeSH secundário: Animais Sítios de Ligação Transporte Biológico Ativo Seres Humanos Modelos Químicos Simulação de Acoplamento Molecular Ligação Proteica Conformação Proteica Especificidade da Espécie Relação Estrutura-Atividade Peixe-Zebra Proteínas de Peixe-Zebra/ultraestrutura [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acids); 0 (Phosphates); 0 (Sodium-Phosphate Cotransporter Proteins, Type II); 0 (Zebrafish Proteins); 9NEZ333N27 (Sodium) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170626 [Lr] Data última revisão: 170626 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161028 [St] Status: MEDLINE [do] DOI: 10.1152/ajpregu.00020.2016

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[PMID]: 27165344 [Au] Autor: Thomas L; Wagner CA; Biber J; Hernando N [Ad] Endereço: NCCR Kidney.CH and Institute of Physiology, University of Zurich, Zurich, Switzerland. [Ti] Título: Adaptation of Opossum Kidney Cells to Luminal Phosphate: Effects of Phosphonoformic Acid and Kinase Inhibitors. [So] Source: Kidney Blood Press Res;41(3):298-310, 2016. [Is] ISSN: 1423-0143 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: BACKGROUND/AIMS: Renal reabsorption of inorganic phosphate (Pi) is mediated by SLC34 and SLC20 Na+/Pi-cotransporters the abundance of which is under hormonal control. Extracellular Pi itself also regulates the expression of cotransporters and the concentration of Pi-regulating hormones, though the signaling pathways are largely unknown. Here, we explored the mechanisms that allow renal proximal cells to adapt to changes in the concentration of Pi. METHODS: opossum kidney (OK) cells, a model of proximal epithelia, were incubated with different concentrations of Pi in the absence/presence of phosphonoformic acid (PFA), a Pi-analogue and SLC34-inhibitor, and of inhibitors of kinases involved in hormonal control of Pi-homeostasis; cells cultured in normal media were treated with uncouplers of oxidative phosphorylation. Then, the intracellular concentration of ATP and/or the Pi-transport capacity of the cultures were analyzed. RESULTS: luminal Pi regulates the Pi-transport and the intracellular ATP levels. Changes in ATP seem secondary to alterations in Pi-transport, rather than ATP acting as a signal. Adaptation of Pi-transport to high Pi was not mimicked by PFA. Transport adaptation was blocked by PFA but not by kinase inhibitors. CONCLUSIONS: in OK cells, adaptation of Pi-transport to luminal Pi does not depend on the same signaling pathways involved in hormonal regulation. [Mh] Termos MeSH primário: Rim/citologia Fosfatos/metabolismo [Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo Animais Transporte Biológico/efeitos dos fármacos Células Cultivadas Foscarnet/antagonistas & inibidores Túbulos Renais Proximais/citologia Gambás Fosfatos/farmacologia Inibidores de Proteínas Quinases/farmacologia Transdução de Sinais Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/antagonistas & inibidores Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Phosphates); 0 (Protein Kinase Inhibitors); 0 (Sodium-Phosphate Cotransporter Proteins, Type II); 364P9RVW4X (Foscarnet); 8L70Q75FXE (Adenosine Triphosphate) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170314 [Lr] Data última revisão: 170314 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160512 [St] Status: MEDLINE [do] DOI: 10.1159/000443432

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[PMID]: 26419064 [Au] Autor: Matvieieva N; Shakhovsky A; Kvasko O; Kuchuk N [Ti] Título: HIGH FREQUENCY GENETIC TRANSFORMATION OF CICHORIUM INTYBUS L. USING nptII GENE AS A SELECTIVE MARKER. [So] Source: Tsitol Genet;49(4):11-6, 2015 Jul-Aug. [Is] ISSN: 0564-3783 [Cp] País de publicação: Ukraine [La] Idioma: eng [Ab] Resumo: Cichorium intybus L. is an important vegetable crop used as salad (leaf form) and for the production of coffee substitutes (root form). At the same time these plants can also be used in biotechnologies for synthesis of pharmaceutical proteins. Here we report the possibility of high frequency Agrobacterium rhizogenes- or A. tumefaciens-mediated transformation of C. intybus L. for construction of transgenic "hairy" roots and plants. The used plasmids contained target human interferonifn-α2b gene, Mycobacterium tuberculosis ESAT6:Ag85B antigene esxA::fbpB(ΔTMD) fused gene and human telomerase reverse transcriptase h Tert gene. Using of nptII gene as a selective one was preferable to the bar gene for chicory. In this case the frequency of transgenic plants or "hairy" roots formation was significantly higher. Cultivation of explants on the medium with Basta in concentration 1-2 mg/l have led to plants death or to significant reduction of number of shoots formed. Frequency of "hairy" roots formation varied from 5.9 to 42.3% after A. rhizogenes-mediated transformation. Frequency of regeneration of transgenic plants varied from 10 to 86% after A. tumefaciens-mediated transformation. Both A. rhizogenes- and A. tumefaciens-mediated transformation frequency depended on the type of explants, roots or cotyledons, and vector used. Usage of A. tumefaciens carrying pCB064 plasmid (target esxA:fbpB(ΔTMD) fused gene and nptII selective gene) resulted in the most effective regeneration of transgenic plants with regeneration frequency up to 86%. In the case of chicory A. rhizogenes-mediated transformation the highest regeneration frequency up to 42.3% was demonstrated using p CB161 vector with ifn-α2b target gene and nptII selective gene. [Mh] Termos MeSH primário: Agrobacterium/genética Chicória/genética Cotilédone/genética Raízes de Plantas/genética Plasmídeos/metabolismo Transformação Genética [Mh] Termos MeSH secundário: Aciltransferases/genética Antígenos de Bactérias/genética Proteínas de Bactérias/genética Chicória/anatomia & histologia Cotilédone/anatomia & histologia Marcadores Genéticos Vetores Genéticos Interferon-alfa/genética Mycobacterium tuberculosis/química Raízes de Plantas/anatomia & histologia Plantas Geneticamente Modificadas Plasmídeos/química Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/genética Telomerase/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, Bacterial); 0 (Bacterial Proteins); 0 (ESAT-6 protein, Mycobacterium tuberculosis); 0 (Genetic Markers); 0 (Interferon-alpha); 0 (Sodium-Phosphate Cotransporter Proteins, Type II); EC 2.3.- (Acyltransferases); EC 2.3.1.- (antigen 85B, Mycobacterium tuberculosis); EC 2.7.7.49 (TERT protein, human); EC 2.7.7.49 (Telomerase) [Em] Mês de entrada: 1512 [Cu] Atualização por classe: 150930 [Lr] Data última revisão: 150930 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151001 [St] Status: MEDLINE

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[PMID]: 25910236 [Au] Autor: Albano G; Moor M; Dolder S; Siegrist M; Wagner CA; Biber J; Hernando N; Hofstetter W; Bonny O; Fuster DG [Ad] Endereço: Division of Nephrology, Hypertension and Clinical Pharmacology, University Hospital of Bern, Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; NCCR Transcure, University of Bern, Bern, Switzerland; NCCR Kidney.CH, University of Zürich, Zürich [Ti] Título: Sodium-dependent phosphate transporters in osteoclast differentiation and function. [So] Source: PLoS One;10(4):e0125104, 2015. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Osteoclasts are multinucleated bone degrading cells. Phosphate is an important constituent of mineralized bone and released in significant quantities during bone resorption. Molecular contributors to phosphate transport during the resorptive activity of osteoclasts have been controversially discussed. This study aimed at deciphering the role of sodium-dependent phosphate transporters during osteoclast differentiation and bone resorption. Our studies reveal RANKL-induced differential expression of sodium-dependent phosphate transport protein IIa (NaPi-IIa) transcript and protein during osteoclast development, but no expression of the closely related NaPi-IIb and NaPi-IIc SLC34 family isoforms. In vitro studies employing NaPi-IIa-deficient osteoclast precursors and mature osteoclasts reveal that NaPi-IIa is dispensable for bone resorption and osteoclast differentiation. These results are supported by the analysis of structural bone parameters by high-resolution microcomputed tomography that yielded no differences between adult NaPi-IIa WT and KO mice. By contrast, both type III sodium-dependent phosphate transporters Pit-1 and Pit-2 were abundantly expressed throughout osteoclast differentiation, indicating that they are the relevant sodium-dependent phosphate transporters in osteoclasts and osteoclast precursors. We conclude that phosphate transporters of the SLC34 family have no role in osteoclast differentiation and function and propose that Pit-dependent phosphate transport could be pivotal for bone resorption and should be addressed in further studies. [Mh] Termos MeSH primário: Diferenciação Celular/fisiologia Osteoclastos/metabolismo Osteoclastos/fisiologia Fosfatos/metabolismo Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo Sódio/metabolismo [Mh] Termos MeSH secundário: Animais Reabsorção Óssea/metabolismo Reabsorção Óssea/fisiopatologia Linhagem Celular Transporte de Íons/fisiologia Camundongos Ligante RANK [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Phosphates); 0 (RANK Ligand); 0 (Sodium-Phosphate Cotransporter Proteins, Type II); 0 (Sodium-Phosphate Cotransporter Proteins, Type III); 9NEZ333N27 (Sodium) [Em] Mês de entrada: 1604 [Cu] Atualização por classe: 150513 [Lr] Data última revisão: 150513 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150425 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0125104

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[PMID]: 25515813 [Au] Autor: Huang T; Lin X; Li Q; Luo W; Song L; Tan X; Wang W; Li X; Wu X [Ad] Endereço: Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632, China. [Ti] Título: Selection of a novel FGF23-binding peptide antagonizing the inhibitory effect of FGF23 on phosphate uptake. [So] Source: Appl Microbiol Biotechnol;99(7):3169-77, 2015 Apr. [Is] ISSN: 1432-0614 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis and has been considered as a potential therapeutic target for hypophosphatemic disorders. Herein, we isolated a novel FGF23-binding peptide by screening a phage display library with FGF23180-205, the minimal epitope of FGF23 binding to the binary fibroblast growth factor receptor (FGFR)-Klotho complex. The corresponding peptide (referred to as 23-b6) showed high homology to the immunoglobulin-like (Ig-like) domain III (D3) of FGFR1c, the predominant receptor mediating the phosphaturic activity of FGF23. The 23-b6 peptide and panning target FGF23180-205 carried opposite charges and shared similar hydrophilic profiles. Functional analysis indicated that synthetic 23-b6 peptide exhibited antagonistic effect on the inhibition of phosphate uptake by FGF23 in opossum kidney cells (OK cells). The mechanisms of 23-b6 peptide impairing the bioactivity of FGF23 involved blockade of the activation of Erk cascade and up-regulation of NaPi-2a and NaPi-2c expression in OK cells. Our results demonstrate that the 23-b6 peptide is a potent FGF23 antagonist with increased effect on phosphate uptake in kidney cells and might have therapeutic potentials in hypophosphatemic disorders characterized by an abnormally high level of FGF23. [Mh] Termos MeSH primário: Fatores de Crescimento de Fibroblastos/metabolismo Biblioteca de Peptídeos Peptídeos/farmacologia Fosfatos/farmacocinética [Mh] Termos MeSH secundário: Animais Células Cultivadas/efeitos dos fármacos Epitopos MAP Quinases Reguladas por Sinal Extracelular/metabolismo Fatores de Crescimento de Fibroblastos/antagonistas & inibidores Fatores de Crescimento de Fibroblastos/farmacologia Glucuronidase/metabolismo Rim/citologia Gambás Peptídeos/metabolismo Fosfatos/metabolismo Proteínas Proto-Oncogênicas c-akt/metabolismo Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/genética Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Epitopes); 0 (Peptide Library); 0 (Peptides); 0 (Phosphates); 0 (Sodium-Phosphate Cotransporter Proteins, Type II); 0 (fibroblast growth factor 23); 62031-54-3 (Fibroblast Growth Factors); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.2.1.31 (Glucuronidase); EC 3.2.1.31 (klotho protein) [Em] Mês de entrada: 1605 [Cu] Atualização por classe: 150319 [Lr] Data última revisão: 150319 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 141218 [St] Status: MEDLINE [do] DOI: 10.1007/s00253-014-6283-5

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[PMID]: 25504050 [Au] Autor: Polóniová Z; Jopcík M; Matusíková I; Libantová J; Moravcíková J [Ad] Endereço: Institute of Plant Genetics and Biotechnology, Slovak Academy of Sciences, Akademicka 2, P.O. Box 39A, 95 007, Nitra, Slovak Republic, zuzana.poloniova@savba.sk. [Ti] Título: The pollen- and embryo-specific Arabidopsis DLL promoter bears good potential for application in marker-free Cre/loxP self-excision strategy. [So] Source: Plant Cell Rep;34(3):469-81, 2015 Mar. [Is] ISSN: 1432-203X [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: KEY MESSAGE: Marker-free transgenic plants can be generated with high efficiency by using the Cre/ lox P self-excision system controlled by the pollen- and embryo-specific Arabidopsis DLL promoter. In this work, we aimed to study the feasibility of using the pollen- and embryo-specific DLL promoter of the At4g16160 gene from Arabidopsis thaliana in a Cre/loxP self-excision strategy. A Cre/loxP self-excision cassette controlled by the DLL promoter was introduced into the tobacco genome via Agrobacterium-mediated transformation. No evidence for premature activation of the Cre/loxP system was observed in primary transformants. The efficiency of nptII removal during pollen and embryo development was investigated in transgenic T1 progenies derived from eight self- and four cross-pollinated T0 lines, respectively. Segregation and rooting assays were performed to select recombined T1 plants. Molecular analyses of these plants confirmed the excision event in all analysed T0 lines and marker-free transgenic T1 plants were obtained with efficiency of up to 96.2%. The Arabidopsis DLL promoter appears to be a strong candidate to drive Cre-mediated recombination not only in tobacco as a model plant, but also in other plant species. [Mh] Termos MeSH primário: Proteínas de Arabidopsis/genética Canais Iônicos/genética Plantas Geneticamente Modificadas Pólen/genética Regiões Promotoras Genéticas/genética Tabaco/genética [Mh] Termos MeSH secundário: Agrobacterium/genética Sequência de Bases Regulação da Expressão Gênica de Plantas Marcadores Genéticos Vetores Genéticos Integrases/genética Dados de Sequência Molecular Sementes/genética Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/genética Transformação Bacteriana [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Arabidopsis Proteins); 0 (Genetic Markers); 0 (Ion Channels); 0 (OEP16-L protein, Arabidopsis); 0 (Sodium-Phosphate Cotransporter Proteins, Type II); EC 2.7.7.- (Cre recombinase); EC 2.7.7.- (Integrases) [Em] Mês de entrada: 1605 [Cu] Atualização por classe: 171004 [Lr] Data última revisão: 171004 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 141216 [St] Status: MEDLINE [do] DOI: 10.1007/s00299-014-1726-0

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[PMID]: 25096800 [Au] Autor: Wu XR [Ad] Endereço: Departments of Urology and Pathology, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA, xue-ru.wu@med.nyu.edu. [Ti] Título: Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall's plaques. [So] Source: Urolithiasis;43 Suppl 1:65-76, 2015 Jan. [Is] ISSN: 2194-7236 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Genetically engineered mouse models (GEMMs) have been highly instrumental in elucidating gene functions and molecular pathogenesis of human diseases, although their use in studying kidney stone formation or nephrolithiasis remains relatively limited. This review intends to provide an overview of several knockout mouse models that develop interstitial calcinosis in the renal papillae. Included herein are mice deficient for Tamm-Horsfall protein (THP; also named uromodulin), osteopontin (OPN), both THP and OPN, Na(+)-phosphate cotransporter Type II (Npt2a) and Na(+)/H(+) exchanger regulatory factor (NHERF-1). The baseline information of each protein is summarized, along with key morphological features of the interstitial calcium deposits in mice lacking these proteins. Attempts are made to correlate the papillary interstitial deposits found in GEMMs with Randall's plaques, the latter considered precursors of idiopathic calcium stones in patients. The pathophysiology that underlies the renal calcinosis in the knockout mice is also discussed wherever information is available. Not all the knockout models are allocated equal space because some are more extensively characterized than others. Despite the inroads already made, the exact physiological underpinning, origin, evolution and fate of the papillary interstitial calcinosis in the GEMMs remain incompletely defined. Greater investigative efforts are warranted to pin down the precise role of the papillary interstitial calcinosis in nephrolithiasis using the existing models. Additionally, more sophisticated, second-generation GEMMs that allow gene inactivation in a time-controlled manner and "compound mice" that bear several genetic alterations are urgently needed, in light of mounting evidence that nephrolithiasis is a multifactorial, multi-stage and polygenic disease. [Mh] Termos MeSH primário: Calcinose/genética Nefropatias/genética Medula Renal [Mh] Termos MeSH secundário: Animais Modelos Animais de Doenças Camundongos/genética Camundongos Knockout Osteopontina/genética Fosfoproteínas/genética Trocadores de Sódio-Hidrogênio/genética Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/genética Uromodulina/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; REVIEW [Nm] Nome de substância: 0 (Phosphoproteins); 0 (Sodium-Hydrogen Exchangers); 0 (Sodium-Phosphate Cotransporter Proteins, Type II); 0 (Umod protein, mouse); 0 (Uromodulin); 0 (sodium-hydrogen exchanger regulatory factor); 106441-73-0 (Osteopontin) [Em] Mês de entrada: 1601 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140807 [St] Status: MEDLINE [do] DOI: 10.1007/s00240-014-0699-3

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[PMID]: 25028980 [Au] Autor: Lederer E [Ad] Endereço: aMedical Services, Robley Rex VA Medical Center bKidney Disease Program, University of Louisville School of Medicine, Louisville, Kentucky, USA. [Ti] Título: Renal phosphate transporters. [So] Source: Curr Opin Nephrol Hypertens;23(5):502-6, 2014 Sep. [Is] ISSN: 1473-6543 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: PURPOSE OF REVIEW: Phosphate homeostasis is tightly controlled by the coordinated activity of bone, kidney, intestine, and parathyroid gland. The renal phosphate transporters have emerged as key regulators of both total body phosphate homeostasis and serum phosphate concentration. This review focuses on the latest updates in phosphate transport and transporters with an emphasis on renal phosphate transporters. RECENT FINDINGS: Structure function analysis of type II sodium phosphate cotransporters has revealed motifs with significant similarity to those seen in other sodium-coupled solute transporters, identifying key amino acid residues important for solute binding and transport. Previously unidentified regulators of these transporters have been found, although their physiologic significance and interaction with more traditional regulators have not been established. Type II and type III sodium phosphate cotransporters play critical roles in bone, choroid plexus, and vascular physiology and pathophysiology. SUMMARY: Increasing knowledge of structure function relationships for sodium phosphate cotransporters, as well as greater appreciation for the complexity of their regulation and role in renal and nonrenal tissue, brings the promise of newer, more specific treatments for disorders of phosphate homeostasis. VIDEO ABSTRACT: http://links.lww.com/CONH/A10. [Mh] Termos MeSH primário: Rim/metabolismo Fosfatos/metabolismo Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo [Mh] Termos MeSH secundário: Animais Transporte Biológico Homeostase Seres Humanos Conformação Proteica Transporte Proteico Transdução de Sinais Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/química Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; REVIEW; VIDEO-AUDIO MEDIA [Nm] Nome de substância: 0 (Phosphates); 0 (Sodium-Phosphate Cotransporter Proteins, Type II) [Em] Mês de entrada: 1504 [Cu] Atualização por classe: 161025 [Lr] Data última revisão: 161025 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140717 [St] Status: MEDLINE [do] DOI: 10.1097/MNH.0000000000000053

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[PMID]: 24655502 [Au] Autor: Fenollar-Ferrer C; Patti M; Knöpfel T; Werner A; Forster IC; Forrest LR [Ad] Endereço: Computational Structural Biology Group, Max Planck Institute of Biophysics, Frankfurt am Main, Germany. [Ti] Título: Structural fold and binding sites of the human Naâ�º-phosphate cotransporter NaPi-II. [So] Source: Biophys J;106(6):1268-79, 2014 Mar 18. [Is] ISSN: 1542-0086 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Phosphate plays essential biological roles and its plasma level in humans requires tight control to avoid bone loss (insufficiency) or vascular calcification (excess). Intestinal absorption and renal reabsorption of phosphate are mediated by members of the SLC34 family of sodium-coupled transporters (NaPi-IIa,b,c) whose membrane expression is regulated by various hormones, circulating proteins, and phosphate itself. Consequently, NaPi-II proteins are also potentially important pharmaceutical targets for controlling phosphate levels. Their crucial role in Pi homeostasis is underscored by pathologies resulting from naturally occurring SLC34 mutations and SLC34 knockout animals. SLC34 isoforms have been extensively studied with respect to transport mechanism and structure-function relationships; however, the three-dimensional structure is unknown. All SLC34 transporters share a duplicated motif comprising a glutamine followed by a stretch of threonine or serine residues, suggesting the presence of structural repeats as found in other transporter families. Nevertheless, standard bioinformatic approaches fail to clearly identify a suitable template for molecular modeling. Here, we used hydrophobicity profiles and hidden Markov models to define a structural repeat common to all SLC34 isoforms. Similar approaches identify a relationship with the core regions in a crystal structure of Vibrio cholerae Na(+)-dicarboxylate transporter VcINDY, from which we generated a homology model of human NaPi-IIa. The aforementioned SLC34 motifs in each repeat localize to the center of the model, and were predicted to form Na(+) and Pi coordination sites. Functional relevance of key amino acids was confirmed by biochemical and electrophysiological analysis of expressed, mutated transporters. Moreover, the validity of the predicted architecture is corroborated by extensive published structure-function studies. The model provides key information for elucidating the transport mechanism and predicts candidate substrate binding sites. [Mh] Termos MeSH primário: Simulação de Dinâmica Molecular Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/química [Mh] Termos MeSH secundário: Motivos de Aminoácidos Sequência de Aminoácidos Sítios de Ligação Seres Humanos Dados de Sequência Molecular Mutação Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/genética Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Sodium-Phosphate Cotransporter Proteins, Type II) [Em] Mês de entrada: 1411 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140325 [St] Status: MEDLINE

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[PMID]: 23652555 [Au] Autor: Uchihashi K; Nakatani T; Goetz R; Mohammadi M; He X; Razzaque MS [Ad] Endereço: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA. [Ti] Título: FGF23-induced hypophosphatemia persists in Hyp mice deficient in the WNT coreceptor Lrp6. [So] Source: Contrib Nephrol;180:124-37, 2013. [Is] ISSN: 1662-2782 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: Deregulated phosphate homeostasis can lead to a wide range of disorders, including myopathy, cardiac dysfunction, and skeletal abnormalities. Therefore, characterization of the molecular regulation of phosphate metabolism is of pathophysiological and clinical significance. Hyp mouse is the model for human X-linked hypophosphatemia which is due to mutations that inactivate the endopeptidases of the X chromosome (PHEX). PHEX inactivation leads to increased serum levels of fibroblast growth factor 23 (FGF23), a phosphaturic hormone that induces excessive renal phosphate excretion and severe hypophosphatemia. The expression of WNT signaling components is increased in Hyp mice. To determine the potential role of WNT signaling in FGF23-mediated hypophosphatemia, we cross-bred Hyp mice with mice deficient in the WNT coreceptor low-density lipoprotein receptor-related protein 6 (Lrp6) to generate Hyp and Lrp6 double mutant mice (Hyp/Lrp6). Like Hyp mice, Hyp/Lrp6 double mutants maintained high serum levels of FGF23, and accordingly exhibited hypophosphatemia to the same degree as the Hyp mice did, indicating that genetically reducing WNT signaling does not impact FGF23-induced phosphaturia. Moreover, similar to Hyp mice, the Hyp/Lrp6 double mutants also exhibited reduced mineralization of the bone, further supporting that reduced WNT signaling does not affect the chronic phosphate wasting caused by excess FGF23 in these mice. In further support of our finding, injection of bioactive FGF23 protein into Lrp6 mutant mice reduced serum phosphate levels to a similar degree as FGF23 injection into wild-type mice. Our in vivo studies provide genetic and pharmacological evidence for a WNT-independent function of FGF23 in the regulation of phosphate homeostasis. [Mh] Termos MeSH primário: Modelos Animais de Doenças Raquitismo Hipofosfatêmico Familiar/fisiopatologia Fatores de Crescimento de Fibroblastos/fisiologia Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência Endopeptidase Neutra Reguladora de Fosfato PHEX/fisiologia Via de Sinalização Wnt [Mh] Termos MeSH secundário: Animais Raquitismo Hipofosfatêmico Familiar/diagnóstico por imagem Raquitismo Hipofosfatêmico Familiar/etiologia Raquitismo Hipofosfatêmico Familiar/genética Fatores de Crescimento de Fibroblastos/sangue Fatores de Crescimento de Fibroblastos/toxicidade Homeostase Hipofosfatemia Familiar/genética Hipofosfatemia Familiar/metabolismo Rim/metabolismo Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia Masculino Camundongos Camundongos Knockout Endopeptidase Neutra Reguladora de Fosfato PHEX/genética Fosfatos/metabolismo Radiografia Proteínas Recombinantes/toxicidade Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/biossíntese Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/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 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Lrp6 protein, mouse); 0 (Phosphates); 0 (Recombinant Proteins); 0 (Sodium-Phosphate Cotransporter Proteins, Type II); 0 (fibroblast growth factor 23); 62031-54-3 (Fibroblast Growth Factors); EC 3.4.24.- (PHEX Phosphate Regulating Neutral Endopeptidase); EC 3.4.24.- (Phex protein, mouse) [Em] Mês de entrada: 1401 [Cu] Atualização por classe: 161125 [Lr] Data última revisão: 161125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130509 [St] Status: MEDLINE [do] DOI: 10.1159/000346792

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