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[PMID]: 28446460 [Au] Autor: Silva I; Costa AF; Moreira S; Ferreirinha F; Magalhães-Cardoso MT; Calejo I; Silva-Ramos M; Correia-de-Sá P [Ad] Endereço: Laboratório de Farmacologia e Neurobiologia, Universidade do Porto, Porto, Portugal. [Ti] Título: Inhibition of cholinergic neurotransmission by ß -adrenoceptors depends on adenosine release and A -receptor activation in human and rat urinary bladders. [So] Source: Am J Physiol Renal Physiol;313(2):F388-F403, 2017 Aug 01. [Is] ISSN: 1522-1466 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The direct detrusor relaxant effect of ß -adrenoceptor agonists as a primary mechanism to improve overactive bladder symptoms has been questioned. Among other targets, activation of ß -adrenoceptors downmodulate nerve-evoked acetylcholine (ACh) release, but there is insufficient evidence for the presence of these receptors on bladder cholinergic nerve terminals. Our hypothesis is that adenosine formed from the catabolism of cyclic AMP in the detrusor may act as a retrograde messenger via prejunctional A receptors to explain inhibition of cholinergic activity by ß -adrenoceptors. Isoprenaline (1 µM) decreased [ H]ACh release from stimulated (10 Hz, 200 pulses) human (-47 ± 5%) and rat (-38 ± 1%) detrusor strips. Mirabegron (0.1 µM, -53 ± 8%) and CL316,243 (1 µM, -37 ± 7%) mimicked isoprenaline (1 µM) inhibition, and their effects were prevented by blocking ß -adrenoceptors with L748,337 (30 nM) and SR59230A (100 nM), respectively, in human and rat detrusor. Mirabegron and isoprenaline increased extracellular adenosine in the detrusor. Blockage of A receptors with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 100 nM) or the equilibrative nucleoside transporters (ENT) with dipyridamole (0.5 µM) prevented mirabegron and isoprenaline inhibitory effects. Dipyridamole prevented isoprenaline-induced adenosine outflow from the rat detrusor, and this effect was mimicked by the ENT1 inhibitor, -(4-nitrobenzyl)-6-thioinosine (NBTI, 30 µM). Cystometry recordings in anesthetized rats demonstrated that SR59230A, DPCPX, dipyridamole, and NBTI reversed the decrease in the voiding frequency caused by isoprenaline (0.1-1,000 nM). Data suggest that inhibition of cholinergic neurotransmission by ß -adrenoceptors results from adenosine release via equilibrative nucleoside transporters and prejunctional A -receptor stimulation in human and rat urinary bladder. [Mh] Termos MeSH primário: Acetilcolina/metabolismo Adenosina/metabolismo Fibras Colinérgicas/metabolismo Inibição Neural Terminações Pré-Sinápticas/metabolismo Receptor A1 de Adenosina/metabolismo Receptores Adrenérgicos beta 3/metabolismo Transmissão Sináptica Bexiga Urinária/inervação [Mh] Termos MeSH secundário: Antagonistas do Receptor A1 de Adenosina/farmacologia Agonistas de Receptores Adrenérgicos beta 3/farmacologia Antagonistas de Receptores Adrenérgicos beta 3/farmacologia Adulto Animais Fibras Colinérgicas/efeitos dos fármacos AMP Cíclico/metabolismo Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo Seres Humanos Técnicas In Vitro Masculino Meia-Idade Inibição Neural/efeitos dos fármacos Inibidores de Fosfodiesterase/farmacologia Terminações Pré-Sinápticas/efeitos dos fármacos Ratos Wistar Receptor A1 de Adenosina/efeitos dos fármacos Receptores Adrenérgicos beta 3/efeitos dos fármacos Transmissão Sináptica/efeitos dos fármacos Fatores de Tempo Micção Urodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ADRB3 protein, human); 0 (Adenosine A1 Receptor Antagonists); 0 (Adrenergic beta-3 Receptor Agonists); 0 (Adrenergic beta-3 Receptor Antagonists); 0 (Equilibrative Nucleoside Transport Proteins); 0 (Phosphodiesterase Inhibitors); 0 (Receptor, Adenosine A1); 0 (Receptors, Adrenergic, beta-3); E0399OZS9N (Cyclic AMP); K72T3FS567 (Adenosine); N9YNS0M02X (Acetylcholine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170918 [Lr] Data última revisão: 170918 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1152/ajprenal.00392.2016

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[PMID]: 27679412 [Au] Autor: Yoshikawa T; Yanai K [Ad] Endereço: Department of Pharmacology, Tohoku University, Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan. tyoshikawa@med.tohoku.ac.jp. [Ti] Título: Histamine Clearance Through Polyspecific Transporters in the Brain. [So] Source: Handb Exp Pharmacol;241:173-187, 2017. [Is] ISSN: 0171-2004 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Histamine plays an important role as a neurotransmitter in diverse brain functions, and clearance of histamine is essential to avoid excessive histaminergic neuronal activity. Histamine N-methyltransferase, which is an enzyme in the central nervous system that metabolizes histamine, is localized to the cytosol. This suggests that a histamine transport process is essential to inactivate histamine. Previous reports have shown the importance of astrocytes for histamine transport, although neuronal histamine transport could not be ruled out. High-affinity and selective histamine transporters have not yet been discovered, although it has been reported that the following three polyspecific transporters transport histamine: organic cation transporter (OCT) 2, OCT3, and plasma membrane monoamine transporter (PMAT). The K values of human OCT2, OCT3, and PMAT are 0.54, 0.64, and 4.4 mM, respectively. The three transporters are expressed in the brain, and their regional distribution is different. Recent studies revealed the contribution of OCT3 and PMAT to histamine transport by primary human astrocytes. Several investigations using mice supported the importance of OCT3 for histamine clearance in the brain. However, further studies are required to elucidate the detailed mechanism of histamine transport in the brain. [Mh] Termos MeSH primário: Transporte Biológico/fisiologia Encéfalo/metabolismo Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo Histamina/metabolismo Fator 3 de Transcrição de Octâmero/metabolismo Proteínas de Transporte de Cátions Orgânicos/metabolismo [Mh] Termos MeSH secundário: Animais Membrana Celular/metabolismo Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Equilibrative Nucleoside Transport Proteins); 0 (Octamer Transcription Factor-3); 0 (Organic Cation Transport Proteins); 820484N8I3 (Histamine) [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: 160929 [St] Status: MEDLINE [do] DOI: 10.1007/164_2016_13

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[PMID]: 27501284 [Au] Autor: Usui T; Nakazawa A; Okura T; Deguchi Y; Akanuma SI; Kubo Y; Hosoya KI [Ad] Endereço: Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. [Ti] Título: Histamine elimination from the cerebrospinal fluid across the blood-cerebrospinal fluid barrier: involvement of plasma membrane monoamine transporter (PMAT/SLC29A4). [So] Source: J Neurochem;139(3):408-418, 2016 Nov. [Is] ISSN: 1471-4159 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The elimination of histamine, an excitatory neurotransmitter, from the brain/CSF across the blood-brain barrier and blood-CSF barrier (BCSFB) was investigated using Wistar rats, which were anesthetized with pentobarbital sodium. An in vivo intracerebral microinjection study suggested that there was only partial efflux of [ H]histamine from the rat brain across the blood-brain barrier. The [ H]histamine elimination clearance from the rat CSF was 3.8-fold greater than that of a CSF bulk flow marker, and the elimination of [ H]histamine was significantly inhibited by the co-administration of unlabeled histamine, suggesting the involvement of a carrier-mediated process in histamine elimination from the CSF. The uptake study of [ H]histamine by the isolated rat choroid plexus revealed histamine elimination from the CSF across the BCSFB. The [ H]histamine uptake by TR-CSFB3 cells, a model cell line for the BCSFB, exhibited temperature-dependent and saturable kinetics, suggesting the involvement of carrier-mediated transport of histamine at the BCSFB. In the inhibition study, [ H]histamine uptake by TR-CSFB3 cells was significantly inhibited by substrates and/or inhibitors of plasma membrane monoamine transporter (PMAT/SLC29A4), but not affected by substrates of organic cation transporters. These results suggest the elimination of histamine from the CSF via plasma membrane monoamine transporter at the BCSFB. [Mh] Termos MeSH primário: Barreira Hematoneural/metabolismo Proteínas de Transporte de Cátions/genética Proteínas de Transporte de Cátions/metabolismo Histamina/líquido cefalorraquidiano [Mh] Termos MeSH secundário: Animais Barreira Hematoencefálica/metabolismo Células CHO Membrana Celular/metabolismo Plexo Corióideo/metabolismo Cricetinae Cricetulus Proteínas de Transporte de Nucleosídeo Equilibrativas Histamina/administração & dosagem Histamina/farmacologia Técnicas In Vitro Injeções Intraventriculares Lopinavir/farmacologia Masculino Microinjeções Inibidores de Proteases/farmacologia Ratos Ratos Wistar [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cation Transport Proteins); 0 (Equilibrative Nucleoside Transport Proteins); 0 (PMAT protein, rat); 0 (Protease Inhibitors); 2494G1JF75 (Lopinavir); 820484N8I3 (Histamine) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160809 [St] Status: MEDLINE [do] DOI: 10.1111/jnc.13758

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[PMID]: 27284054 [Au] Autor: Young JD [Ad] Endereço: Membrane Protein Research Group, Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 james.young@ualberta.ca. [Ti] Título: The SLC28 (CNT) and SLC29 (ENT) nucleoside transporter families: a 30-year collaborative odyssey. [So] Source: Biochem Soc Trans;44(3):869-76, 2016 Jun 15. [Is] ISSN: 1470-8752 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Specialized nucleoside transporter (NT) proteins are required for passage of nucleosides and hydrophilic nucleoside analogues across biological membranes. Physiologic nucleosides serve as central salvage metabolites in nucleotide biosynthesis, and nucleoside analogues are used as chemotherapeutic agents in the treatment of cancer and antiviral diseases. The nucleoside adenosine modulates numerous cellular events via purino-receptor cell signalling pathways. Human NTs are divided into two structurally unrelated protein families: the SLC28 concentrative nucleoside transporter (CNT) family and the SLC29 equilibrative nucleoside transporter (ENT) family. Human CNTs are inwardly directed Na(+)-dependent nucleoside transporters found predominantly in intestinal and renal epithelial and other specialized cell types. Human ENTs mediate bidirectional fluxes of purine and pyrimidine nucleosides down their concentration gradients and are ubiquitously found in most, possibly all, cell types. Both protein families are evolutionarily old: CNTs are present in both eukaryotes and prokaryotes; ENTs are widely distributed in mammalian, lower vertebrate and other eukaryote species. This mini-review describes a 30-year collaboration with Professor Stephen Baldwin to identify and understand the structures and functions of these physiologically and clinically important transport proteins. [Mh] Termos MeSH primário: Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo Proteínas de Membrana Transportadoras/metabolismo [Mh] Termos MeSH secundário: Animais Bactérias/metabolismo Transporte Biológico Proteínas de Transporte de Nucleosídeo Equilibrativas/fisiologia Eucariotos/metabolismo Seres Humanos Proteínas de Membrana Transportadoras/fisiologia Nucleosídeos/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Equilibrative Nucleoside Transport Proteins); 0 (Membrane Transport Proteins); 0 (Nucleosides); 0 (cif nucleoside transporter) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170605 [Lr] Data última revisão: 170605 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160611 [St] Status: MEDLINE [do] DOI: 10.1042/BST20160038

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[PMID]: 26979520 [Au] Autor: El Messaoudi S; Russel FG; Colbers A; Bandell CC; van den Broek PH; Burger DM; Rongen GA; Riksen NP [Ad] Endereço: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands. [Ti] Título: The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers. [So] Source: Eur J Clin Pharmacol;72(6):725-30, 2016 Jun. [Is] ISSN: 1432-1041 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: PURPOSE: Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin. METHODS: Eighteen healthy volunteers (mean age 23 years; 9 male) were randomized in an open-label crossover study. Subjects were allocated to treatment with metformin 500 mg twice daily in combination with dipyridamole slow-release 200 mg twice daily or to metformin alone for 4 days. After a washout period of 10 days, the volunteers were crossed over to the alternative treatment arm. Blood samples were collected during a 10-h period after intake of the last metformin dose. The primary endpoint was the area under the plasma concentration-time curve (AUC0-12h) and the maximum plasma metformin concentration (C max). RESULTS: In healthy subjects, dipyridamole did not significantly affect Cmax nor AUC0-12h of metformin under steady-state conditions. CONCLUSIONS: Previous in vitro studies report that dipyridamole inhibits the ENT4 transporter that mediates gastrointestinal uptake of metformin. In contrast, co-administration of dipyridamole at therapeutic dosages to healthy volunteers does not have a clinically relevant effect on metformin plasma steady-state exposure. This observation is reassuring for patients who are treated with this combination of drugs. [Mh] Termos MeSH primário: Dipiridamol/farmacologia Hipoglicemiantes/farmacocinética Metformina/farmacocinética Inibidores da Agregação de Plaquetas/farmacologia [Mh] Termos MeSH secundário: Adulto Estudos Cross-Over Dipiridamol/efeitos adversos Proteínas de Transporte de Nucleosídeo Equilibrativas/antagonistas & inibidores Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo Feminino Voluntários Saudáveis Seres Humanos Hipoglicemiantes/efeitos adversos Hipoglicemiantes/sangue Masculino Metformina/efeitos adversos Metformina/sangue Inibidores da Agregação de Plaquetas/efeitos adversos Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 (Equilibrative Nucleoside Transport Proteins); 0 (Hypoglycemic Agents); 0 (Platelet Aggregation Inhibitors); 0 (SLC29A4 protein, human); 64ALC7F90C (Dipyridamole); 9100L32L2N (Metformin) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160317 [St] Status: MEDLINE [do] DOI: 10.1007/s00228-016-2039-8

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[PMID]: 26376205 [Au] Autor: Wu KC; Lu YH; Peng YH; Hsu LC; Lin CJ [Ad] Endereço: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. [Ti] Título: Effects of lipopolysaccharide on the expression of plasma membrane monoamine transporter (PMAT) at the blood-brain barrier and its implications to the transport of neurotoxins. [So] Source: J Neurochem;135(6):1178-88, 2015 Dec. [Is] ISSN: 1471-4159 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Plasma membrane monoamine transporter (PMAT) is a polyspecific organic cation transporter that is highly expressed in the central nervous system. This study aimed to investigate the effect of lipopolysaccharide on PMAT expression at the blood-brain barrier and the interaction between PMAT and neurotoxins. As a result, PMAT mRNA was identified in brain microvessels (BMVs), brain microvascular endothelial cells (BMECs), astrocytes, and pericytes isolated from C57BL/6 mice and/or Wistar rats using RT-qPCR. The immunofluorescence staining confirmed the expression of PMAT protein in BMVs and striatum of C57BL/6 mice. Western blotting demonstrated its localization at the luminal and abluminal sides of BMECs. In C57BL/6 mice, PMAT protein was significantly increased in BMVs 24 h after an intraperitoneal injection of 3 mg/kg lipopolysaccharide. Lipopolysaccharide treatment also significantly increased PMAT expression in cerebral cortex and the striatum in a time-dependent manner, as well as the brain-to-plasma ratio of 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-benzyl-TIQ). In isolated cells, lipopolysaccharide treatment significantly increased PMAT mRNA in brain astrocytes and the BMECs co-cultured with astrocytes. In addition to 1-methyl-4-phenylpyridinium, the kinetic study indicated that both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-benzyl-TIQ are substrates of human PMAT. These findings suggest that inflammation can change PMAT expression at the blood-brain barrier, which may affect PMAT-mediated transport of neurotoxins. We demonstrated the expression of plasma membrane monoamine transporter (PMAT; mRNA or protein) at several subunits of the blood-brain barrier. Lipopolysaccharide treatment can significantly increase the expression of PMAT in vivo (in brain microvessels, cerebral cortex, and the striatum of C57BL/6 mice) and in vitro (in brain astrocytes and brain microvascular endothelial cells co-cultured with astrocytes). Lipopolysaccharide treatment also increased the brain-to-plasma ratio of 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-benzyl-TIQ) in mice, where 1-benzyl-TIQ competitively inhibited 1-methyl-4-phenylpyridinium (MPP(+)) uptake in MDCK-human PMAT (hPMAT) cells and its uptake in MDCK-hPMAT is concentration dependent. [Mh] Termos MeSH primário: Barreira Hematoencefálica/metabolismo Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo Lipopolissacarídeos/farmacologia Neurotoxinas/metabolismo [Mh] Termos MeSH secundário: Animais Transporte Biológico/efeitos dos fármacos Barreira Hematoencefálica/efeitos dos fármacos Encéfalo/efeitos dos fármacos Encéfalo/metabolismo Membrana Celular/efeitos dos fármacos Membrana Celular/metabolismo Células Cultivadas Seres Humanos Masculino Camundongos Endogâmicos C57BL Proteínas de Transporte de Cátions Orgânicos/metabolismo Ratos Wistar [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Equilibrative Nucleoside Transport Proteins); 0 (Lipopolysaccharides); 0 (Neurotoxins); 0 (Organic Cation Transport Proteins); 0 (SLC29A4 protein, human) [Em] Mês de entrada: 1608 [Cu] Atualização por classe: 160115 [Lr] Data última revisão: 160115 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150917 [St] Status: MEDLINE [do] DOI: 10.1111/jnc.13363

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[PMID]: 26285765 [Au] Autor: Duan H; Hu T; Foti RS; Pan Y; Swaan PW; Wang J [Ad] Endereço: Department of Pharmaceutics, University of Washington, Seattle, Washington (H.D., T.H., J.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington (R.S.F.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (Y.P., P.W.S.). [Ti] Título: Potent and Selective Inhibition of Plasma Membrane Monoamine Transporter by HIV Protease Inhibitors. [So] Source: Drug Metab Dispos;43(11):1773-80, 2015 Nov. [Is] ISSN: 1521-009X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Plasma membrane monoamine transporter (PMAT) is a major uptake-2 monoamine transporter that shares extensive substrate and inhibitor overlap with organic cation transporters 1-3 (OCT1-3). Currently, there are no PMAT-specific inhibitors available that can be used in in vitro and in vivo studies to differentiate between PMAT and OCT activities. In this study, we showed that IDT307 (4-(4-(dimethylamino)phenyl)-1-methylpyridinium iodide), a fluorescent analog of 1-methyl-4-phenylpyridinium (MPP+), is a transportable substrate for PMAT and that IDT307-based fluorescence assay can be used to rapidly identify and characterize PMAT inhibitors. Using the fluorescent substrate-based assays, we analyzed the interactions of eight human immunodeficiency virus (HIV) protease inhibitors (PIs) with human PMAT and OCT1-3 in human embryonic kidney 293 (HEK293) cells stably transfected with individual transporters. Our data revealed that PMAT and OCTs exhibit distinct sensitivity and inhibition patterns toward HIV PIs. PMAT is most sensitive to PI inhibition whereas OCT2 and OCT3 are resistant. OCT1 showed an intermediate sensitivity and a distinct inhibition profile from PMAT. Importantly, lopinavir is a potent PMAT inhibitor and exhibited >120 fold selectivity toward PMAT (IC50 = 1.4 ± 0.2 µM) over OCT1 (IC50 = 174 ± 40 µM). Lopinavir has no inhibitory effect on OCT2 or OCT3 at maximal tested concentrations. Lopinavir also exhibited no or much weaker interactions with uptake-1 monoamine transporters. Together, our results reveal that PMAT and OCTs have distinct specificity exemplified by their differential interaction with HIV PIs. Further, we demonstrate that lopinavir can be used as a selective PMAT inhibitor to differentiate PMAT-mediated monoamine and organic cation transport from those mediated by OCT1-3. [Mh] Termos MeSH primário: Proteínas de Transporte de Nucleosídeo Equilibrativas/antagonistas & inibidores Inibidores da Protease de HIV/farmacologia Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores Transportador 1 de Cátions Orgânicos/antagonistas & inibidores [Mh] Termos MeSH secundário: Transporte Biológico/efeitos dos fármacos Transporte Biológico/fisiologia Relação Dose-Resposta a Droga Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo Células HEK293 Seres Humanos Proteínas de Transporte de Cátions Orgânicos/metabolismo Transportador 1 de Cátions Orgânicos/metabolismo Transportador 2 de Cátion Orgânico [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Equilibrative Nucleoside Transport Proteins); 0 (HIV Protease Inhibitors); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 1); 0 (Organic Cation Transporter 2); 0 (SLC22A2 protein, human); 0 (SLC29A4 protein, human); 0 (solute carrier family 22 (organic cation transporter), member 3) [Em] Mês de entrada: 1607 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150820 [St] Status: MEDLINE [do] DOI: 10.1124/dmd.115.064824

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[PMID]: 26080001 [Au] Autor: Girke C; Arutyunova E; Syed M; Traub M; Möhlmann T; Lemieux MJ [Ad] Endereço: Department of Plant Physiology, University of Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany. Electronic address: girke@rhrk.uni-kl.de. [Ti] Título: High yield expression and purification of equilibrative nucleoside transporter 7 (ENT7) from Arabidopsis thaliana. [So] Source: Biochim Biophys Acta;1850(9):1921-9, 2015 Sep. [Is] ISSN: 0006-3002 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: BACKGROUND: Equilibrative nucleoside transporters (ENTs) facilitate the import of nucleosides and their analogs into cells in a bidirectional, non-concentrative manner. However, in contrast to their name, most characterized plant ENTs act in a concentrative manner. A direct characterization of any ENT protein has been hindered due to difficulties in overexpression and obtaining pure recombinant protein. METHODS: The equilibrative nucleoside transporter 7 from Arabidopsis thaliana (AtENT7) was expressed in Xenopus laevis oocytes to assess mechanism of substrate uptake. Recombinant protein fused to enhanced green fluorescent protein (eGFP) was expressed in Pichia pastoris to characterize its oligomeric state by gel filtration and substrate binding by microscale thermophoresis (MST). RESULTS: AtENT7 expressed in X. laevis oocytes works as a classic equilibrative transporter. The expression of AtENT7-eGFP in the P. pastoris system yielded milligram amounts of pure protein that exists as stable homodimers. The concentration dependent binding of purine and pyrimidine nucleosides to the purified recombinant protein, assessed by MST, confirmed that AtENT7-eGFP is properly folded. For the first time the binding of nucleobases was observed for AtENT7. SIGNIFICANCE: The availability of pure recombinant AtENT7 will permit detailed kinetic and structural studies of this unique member of the ENT family and, given the functional similarity to mammalian ENTs, will serve as a good model for understanding the structural basis of translocation mechanism for the family. [Mh] Termos MeSH primário: Arabidopsis/metabolismo Proteínas de Transporte de Nucleosídeo Equilibrativas/genética Proteínas Recombinantes/biossíntese [Mh] Termos MeSH secundário: Animais Proteínas de Transporte de Nucleosídeo Equilibrativas/isolamento & purificação Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo Oócitos Xenopus laevis/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Equilibrative Nucleoside Transport Proteins); 0 (Recombinant Proteins) [Em] Mês de entrada: 1509 [Cu] Atualização por classe: 161126 [Lr] Data última revisão: 161126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150617 [St] Status: MEDLINE

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[PMID]: 26070128 [Au] Autor: Yang C; Leung GP [Ad] Endereço: *Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, China; and †Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. [Ti] Título: Equilibrative Nucleoside Transporters 1 and 4: Which One Is a Better Target for Cardioprotection Against Ischemia-Reperfusion Injury? [So] Source: J Cardiovasc Pharmacol;65(6):517-21, 2015 Jun. [Is] ISSN: 1533-4023 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The cardioprotective effects of adenosine and adenosine receptor agonists have been studied extensively. However, their therapeutic outcomes in ischemic heart disease are limited by systemic side effects such as hypotension, bradycardia, and sedation. Equilibrative nucleoside transporter (ENT) inhibitors may be an alternative. By reducing the uptake of extracellular adenosine, ENT1 inhibitors potentiate the cardioprotective effect of endogenous adenosine. They have fewer systemic side effects because they selectively increase the extracellular adenosine levels in ischemic tissues undergoing accelerated adenosine formation. Nonetheless, long-term inhibition of ENT1 may adversely affect tissues that have low capacity for de novo nucleotide biosynthesis. ENT1 inhibitors may also affect the cellular transport, and hence the efficacy, of anticancer and antiviral nucleoside analogs used in chemotherapy. It has been proposed that ENT4 may also contribute to the regulation of extracellular adenosine in the heart, especially under the acidotic conditions associated with ischemia. Like ENT1 inhibitors, ENT4 inhibitors should work specifically on ischemic tissues. Theoretically, ENT4 inhibitors do not affect tissues that rely on ENT1 for de novo nucleotide synthesis. They also have no interaction with anticancer and antiviral nucleosides. Development of specific ENT4 inhibitors may open a new avenue in research on ischemic heart disease therapy. [Mh] Termos MeSH primário: Desenho de Drogas Proteínas de Transporte de Nucleosídeo Equilibrativas/antagonistas & inibidores Transportador Equilibrativo 1 de Nucleosídeo/antagonistas & inibidores Traumatismo por Reperfusão Miocárdica/prevenção & controle Miócitos Cardíacos/efeitos dos fármacos Substâncias Protetoras/uso terapêutico [Mh] Termos MeSH secundário: Adenosina/metabolismo Animais Citoproteção Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo Transportador Equilibrativo 1 de Nucleosídeo/metabolismo Seres Humanos Terapia de Alvo Molecular Traumatismo por Reperfusão Miocárdica/metabolismo Traumatismo por Reperfusão Miocárdica/patologia Miócitos Cardíacos/metabolismo Miócitos Cardíacos/patologia Transdução de Sinais/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Equilibrative Nucleoside Transport Proteins); 0 (Equilibrative Nucleoside Transporter 1); 0 (Protective Agents); 0 (SLC29A1 protein, human); 0 (SLC29A4 protein, human); K72T3FS567 (Adenosine) [Em] Mês de entrada: 1603 [Cu] Atualização por classe: 150620 [Lr] Data última revisão: 150620 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150613 [St] Status: MEDLINE [do] DOI: 10.1097/FJC.0000000000000194

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MEDLINE

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[PMID]: 25694117 [Au] Autor: Hosford PS; Millar J; Ramage AG [Ad] Endereço: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. [Ti] Título: Cardiovascular afferents cause the release of 5-HT in the nucleus tractus solitarii; this release is regulated by the low- (PMAT) not the high-affinity transporter (SERT). [So] Source: J Physiol;593(7):1715-29, 2015 Apr 01. [Is] ISSN: 1469-7793 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The nucleus tractus solitarii (NTS) integrates inputs from cardiovascular afferents and thus is crucial for cardiovascular homeostasis. These afferents primarily release glutamate, although 5-HT has also been shown to play a role in their actions. Using fast-cyclic voltammetry, an increase in 5-HT concentrations (range 12-50 nm) could be detected in the NTS in anaesthetized rats in response to electrical stimulation of the vagus and activation of cardiopulmonary, chemo- and baroreceptor reflexes. This 5-HT signal was not potentiated by the serotonin transporter (SERT) or the noradrenaline transporter (NET) inhibitors citalopram and desipramine (1 mg kg(-1) ). However, decynium-22 (600 µg kg(-1) ), an organic cation 3 transporter (OCT3)/plasma membrane monoamine transporter (PMAT) inhibitor, increased the 5-HT signal by 111 ± 21% from 29 ± 10 nm. The effectiveness of these inhibitors was tested against the removal time of 5-HT and noradrenaline applied by microinjection to the NTS. Citalopram and decynium-22 attenuated the removal of 5-HT but not noradrenaline, whereas desipramine had the reverse action. The OCT3 inhibitor corticosterone (10 mg kg(-1) ) had no effect. Blockade of glutamate receptors with topical kynurenate (10-50 nm) reduced the vagally evoked 5-HT signal by 50%, indicating that this release was from at least two sources. It is concluded that vagally evoked 5-HT release is under the regulation of the high-capacity, low-affinity transporter PMAT, not the low-capacity, high-affinity transporter SERT. This is the first demonstration that PMAT may be playing a physiological role in the regulation of 5-HT transmission and this could indicate that 5-HT is acting, in part, as a volume transmitter within the NTS. [Mh] Termos MeSH primário: Proteínas de Transporte de Nucleosídeo Equilibrativas/fisiologia Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia Serotonina/fisiologia Núcleo Solitário/fisiologia [Mh] Termos MeSH secundário: Animais Pressão Sanguínea/efeitos dos fármacos Citalopram/farmacologia Desipramina/farmacologia Estimulação Elétrica Proteínas de Transporte de Nucleosídeo Equilibrativas/antagonistas & inibidores Frequência Cardíaca/efeitos dos fármacos Ácido Cinurênico/farmacologia Masculino Norepinefrina/farmacologia Quinolinas/farmacologia Ratos Sprague-Dawley Inibidores da Captação de Serotonina/farmacologia Núcleo Solitário/efeitos dos fármacos Nervo Vago/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Equilibrative Nucleoside Transport Proteins); 0 (Quinolines); 0 (Serotonin Plasma Membrane Transport Proteins); 0 (Serotonin Uptake Inhibitors); 0DHU5B8D6V (Citalopram); 20766-49-8 (pseudoisocyanine); 333DO1RDJY (Serotonin); H030S2S85J (Kynurenic Acid); TG537D343B (Desipramine); X4W3ENH1CV (Norepinephrine) [Em] Mês de entrada: 1601 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150220 [St] Status: MEDLINE [do] DOI: 10.1113/jphysiol.2014.285312

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