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Pesquisa : D12.776.157.530.562.374 [Categoria DeCS]
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[PMID]:28483526
[Au] Autor:Luo D; Chen L; Yu B
[Ad] Endereço:Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China; Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, China.
[Ti] Título:Inhibition of the high affinity choline transporter enhances hyperalgesia in a rat model of chronic pancreatitis.
[So] Source:Biochem Biophys Res Commun;488(1):204-210, 2017 Jun 17.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The mechanisms underlying chronic and persistent pain associated with chronic pancreatitis (CP) are not completely understood. The cholinergic system is one of the major neural pathways of the pancreas. Meanwhile, this system plays an important role in chronic pain. We hypothesized that the high affinity choline transporter CHT1, which is a main determinant of cholinergic signaling capacity, is involved in regulating pain associated with CP. METHODS: CP was induced by intraductal injection of 2% trinitrobenzene sulfonic acid (TNBS) in Sprague-Dawley rats. Pathological examination was used to evaluate the inflammation of pancreas and hyperalgesia was assessed by measuring the number of withdrawal events evoked by application of the von Frey filaments. CHT1 expression in pancreas-specific dorsal root ganglia (DRGs) was assessed through immunohistochemistry and western blotting. We also intraperitoneally injected the rats with hemicholinium-3 (HC-3, a specific inhibitor of CHT1). Then we observed its effects on the visceral hyperalgesia induced by CP, and on the acetylcholine (ACh) levels in the DRGs through using an acetylcholine/acetylcholinesterase assay kit. RESULTS: Signs of CP were observed 21 days after TNBS injection. Rats subjected to TNBS infusions had increased sensitivity to mechanical stimulation of the abdomen. CHT1-immunoreactive cells were increased in the DRGs from rats with CP compared to naive or sham rats. Western blots indicated that CHT1 expression was significantly up-regulated in TNBS-treated rats when compared to naive or sham-operated rats at all time points following surgery. In the TNBS group, CHT1 expression was higher on day 28 than on day 7 or day 14, but there was no statistical difference in CHT1 expression on day 28 vs. day 21. Treatment with HC-3 (60 µg/kg, 80 µg/kg, or 100 µg/kg) markedly enhanced the mechanical hyperalgesia and reduced ACh levels in a dose-dependent manner in rats with CP. CONCLUSION: We report for the first time that CHT1 may be involved in pain modulation in CP, as it plays an important role in pain inhibition. Increased CHT1 activity or the up-regulation of its expression may be used to treat pain in patients with CP.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Hemicolínio 3/farmacologia
Hiperalgesia/metabolismo
Proteínas do Tecido Nervoso/antagonistas & inibidores
Pancreatite Crônica/metabolismo
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Hemicolínio 3/administração & dosagem
Hiperalgesia/patologia
Injeções Intraperitoneais
Masculino
Proteínas do Tecido Nervoso/metabolismo
Pancreatite Crônica/induzido quimicamente
Pancreatite Crônica/patologia
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
Ácido Trinitrobenzenossulfônico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nerve Tissue Proteins); 0 (Plasma Membrane Neurotransmitter Transport Proteins); 147652-48-0 (Slc6a8 protein, rat); 312-45-8 (Hemicholinium 3); 8T3HQG2ZC4 (Trinitrobenzenesulfonic Acid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE


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[PMID]:28320858
[Au] Autor:Stolzenberg S; Li Z; Quick M; Malinauskaite L; Nissen P; Weinstein H; Javitch JA; Shi L
[Ad] Endereço:From the Computational Molecular Biology Group, Institute for Mathematics, Freie Universität Berlin, 14195 Berlin, Germany.
[Ti] Título:The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state.
[So] Source:J Biol Chem;292(18):7372-7384, 2017 May 05.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by the reuptake of released neurotransmitters. This active accumulation of substrate against its concentration gradient is driven by the transmembrane Na gradient and requires that the transporter traverses several conformational states. LeuT, a prokaryotic NSS homolog, has been crystallized in outward-open, outward-occluded, and inward-open states. Two crystal structures of another prokaryotic NSS homolog, the multihydrophobic amino acid transporter (MhsT) from , have been resolved in novel inward-occluded states, with the extracellular vestibule closed and the intracellular portion of transmembrane segment 5 (TM5i) in either an unwound or a helical conformation. We have investigated the potential involvement of TM5i in binding and unbinding of Na2, the Na bound in the Na2 site, by carrying out comparative molecular dynamics simulations of the models derived from the two MhsT structures. We find that the helical TM5i conformation is associated with a higher propensity for Na2 release, which leads to the repositioning of the N terminus and transition to an inward-open state. By using comparative interaction network analysis, we also identify allosteric pathways connecting TM5i and the Na2 binding site to the extracellular and intracellular regions. Based on our combined computational and mutagenesis studies of MhsT and LeuT, we propose that TM5i plays a key role in Na2 binding and release associated with the conformational transition toward the inward-open state, a role that is likely to be shared across the NSS family.
[Mh] Termos MeSH primário: Bacillus/química
Proteínas de Bactérias/química
Simulação de Dinâmica Molecular
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/química
Sódio/química
[Mh] Termos MeSH secundário: Regulação Alostérica
Sistemas de Transporte de Aminoácidos
Bacillus/metabolismo
Proteínas de Bactérias/metabolismo
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo
Domínios Proteicos
Sódio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport Systems); 0 (Bacterial Proteins); 0 (Plasma Membrane Neurotransmitter Transport Proteins); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170607
[Lr] Data última revisão:
170607
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.757153


  3 / 232 MEDLINE  
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[PMID]:28318542
[Au] Autor:De Felice LJ
[Ad] Endereço:Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23284, USA.
[Ti] Título:Monoamine Transporters as Ionotropic Receptors.
[So] Source:Trends Neurosci;40(4):195-196, 2017 Apr.
[Is] ISSN:1878-108X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It is well established that glutamate and GABA signal through both ionotropic and metabotropic receptors. Conversely, it is thought that, with one exception, monoamines (dopamine, serotonin, and norepinephrine) signal via metabotropic receptors. Given their capacity to generate fast-acting currents, I suggest that the monoamine transporters should be considered as ionotropic receptors.
[Mh] Termos MeSH primário: Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo
Receptores Ionotrópicos de Glutamato/metabolismo
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Mh] Termos MeSH secundário: Animais
Neurônios/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Plasma Membrane Neurotransmitter Transport Proteins); 0 (Receptors, Ionotropic Glutamate); 0 (Vesicular Monoamine Transport Proteins)
[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:170321
[St] Status:MEDLINE


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[PMID]:27966884
[Au] Autor:Grouleff J; Koldsø H; Miao Y; Schiøtt B
[Ad] Endereço:Center for Insoluble Protein Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University , Langelandsgade 140, 8000 Aarhus C, Denmark.
[Ti] Título:Ligand Binding in the Extracellular Vestibule of the Neurotransmitter Transporter Homologue LeuT.
[So] Source:ACS Chem Neurosci;8(3):619-628, 2017 Mar 15.
[Is] ISSN:1948-7193
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The human monoamine transporters (MATs) facilitate the reuptake of monoamine neurotransmitters from the synaptic cleft. MATs are linked to a number of neurological diseases and are the targets of both therapeutic and illicit drugs. Until recently, no high-resolution structures of the human MATs existed, and therefore, studies of this transporter family have relied on investigations of the homologues bacterial transporters such as the leucine transporter LeuT, which has been crystallized in several conformational states. A two-substrate transport mechanism has been suggested for this transporter family, which entails that high-affinity binding of a second substrate in an extracellular site is necessary for the substrate in the central binding site to be transported. Compelling evidence for this mechanism has been presented, however, a number of equally compelling accounts suggest that the transporters function through a mechanism involving only a single substrate and a single high-affinity site. To shed light on this apparent contradiction, we have performed extensive molecular dynamics simulations of LeuT in the outward-occluded conformation with either one or two substrates bound to the transporter. We have also calculated the substrate binding affinity in each of the two proposed binding sites through rigorous free energy simulations. Results show that substrate binding is unstable in the extracellular vestibule and the substrate binding affinity within the suggested extracellular site is very low (0.2 and 3.3 M for the two dominant binding modes) compared to the central substrate binding site (14 nM). This suggests that for LeuT in the outward-occluded conformation only a single high-affinity substrate binding site exists.
[Mh] Termos MeSH primário: Leucina/química
Modelos Moleculares
Simulação de Dinâmica Molecular
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação/efeitos dos fármacos
Sítios de Ligação/fisiologia
Espaço Extracelular/metabolismo
Seres Humanos
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/química
Análise de Componente Principal
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Plasma Membrane Neurotransmitter Transport Proteins); GMW67QNF9C (Leucine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161215
[St] Status:MEDLINE
[do] DOI:10.1021/acschemneuro.6b00359


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[PMID]:27456268
[Au] Autor:Romer SH; Seedle K; Turner SM; Li J; Baccei ML; Crone SA
[Ad] Endereço:Division of Neurosurgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229.
[Ti] Título:Accessory respiratory muscles enhance ventilation in ALS model mice and are activated by excitatory V2a neurons.
[So] Source:Exp Neurol;287(Pt 2):192-204, 2017 Jan.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inspiratory accessory respiratory muscles (ARMs) enhance ventilation when demands are high, such as during exercise and/or pathological conditions. Despite progressive degeneration of phrenic motor neurons innervating the diaphragm, amyotrophic lateral sclerosis (ALS) patients and rodent models are able to maintain ventilation at early stages of disease. In order to assess the contribution of ARMs to respiratory compensation in ALS, we examined the activity of ARMs and ventilation throughout disease progression in SOD1 ALS model mice at rest using a combination of electromyography and unrestrained whole body plethysmography. Increased ARM activity, accompanied by increased ventilation, is observed beginning at the onset of symptoms. However, ARM recruitment fails to occur at rest at late stages of disease, even though the same ARMs are used for other behaviors. Using a chemogenetic approach, we demonstrate that a glutamatergic class of neurons in the brainstem and spinal cord, the V2a class, is sufficient to drive increased ARM activity at rest in healthy mice. Additionally, we reveal pathology in the medial reticular formation of the brainstem of SOD1 mice using immunohistochemistry and confocal imaging. Both spinal and brainstem V2a neurons degenerate in ALS model mice, accompanied by regional activation of astrocytes and microglia. These results establish inspiratory ARM recruitment as one of the compensatory mechanisms that maintains breathing at early stages of disease and indicate that V2a neuron degeneration may contribute to ARM failure at late stages of disease.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/patologia
Regulação da Expressão Gênica/genética
Interneurônios/fisiologia
Respiração
Músculos Respiratórios/fisiopatologia
Medula Espinal/patologia
[Mh] Termos MeSH secundário: Esclerose Amiotrófica Lateral/genética
Animais
Antígenos CD/metabolismo
Antígenos de Diferenciação Mielomonocítica/metabolismo
Tronco Encefálico/patologia
Clozapina/análogos & derivados
Clozapina/farmacologia
Modelos Animais de Doenças
Regulação da Expressão Gênica/efeitos dos fármacos
Proteína Glial Fibrilar Ácida/metabolismo
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/metabolismo
Seres Humanos
Masculino
Potenciais da Membrana/efeitos dos fármacos
Potenciais da Membrana/genética
Camundongos
Camundongos Transgênicos
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo
Receptor Muscarínico M3
Receptores Muscarínicos/genética
Receptores Muscarínicos/metabolismo
Respiração/genética
Superóxido Dismutase/genética
Superóxido Dismutase/metabolismo
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Antigens, Differentiation, Myelomonocytic); 0 (CD68 antigen, human); 0 (CHRM3 protein, human); 0 (Glial Fibrillary Acidic Protein); 0 (Homeodomain Proteins); 0 (Plasma Membrane Neurotransmitter Transport Proteins); 0 (Receptor, Muscarinic M3); 0 (Receptors, Muscarinic); 0 (Transcription Factors); 0 (Vsx2 protein, mouse); EC 1.15.1.1 (SOD1 G93A protein); EC 1.15.1.1 (Superoxide Dismutase); J60AR2IKIC (Clozapine); MZA8BK588J (clozapine N-oxide)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160727
[St] Status:MEDLINE


  6 / 232 MEDLINE  
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[PMID]:26732502
[Au] Autor:Tomcik KA; Smiles WJ; Camera DM; Hügel HM; Hawley JA; Watts R
[Ad] Endereço:Centre for Exercise and Nutrition, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, 3065, Australia.
[Ti] Título:Fenugreek increases insulin-stimulated creatine content in L6C11 muscle myotubes.
[So] Source:Eur J Nutr;56(3):973-979, 2017 Apr.
[Is] ISSN:1436-6215
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Creatine uptake by muscle cells is increased in the presence of insulin. Accordingly, compounds with insulin-like actions may also augment creatine uptake. The aim of this study was to investigate whether Trigonella foenum-graecum (fenugreek), an insulin mimetic, increases total intracellular creatine levels in vitro. METHODS: Total cellular creatine content was measured fluorometrically in L6C11 muscle myotubes treated for 1, 4, and 24 h with 0.5 mM creatine (CR), CR and 20 µg/mL fenugreek seed extract (CR + FEN), CR and 100 nM insulin (CR + INS), and CR + INS + FEN (n = 6 per treatment group). Alterations in the expression of the sodium- and chloride-dependent creatine transporter, SLC6A8, and key signaling proteins in the PI3-K/Akt pathway were determined. RESULTS: Compared to control (CON), CR + INS + FEN increased total creatine content after 4 h (P < 0.05), whereas all conditions increased SLC6A8 protein expression above CON at this time (P < 0.05). Changes in insulin signaling were demonstrated via increases in Akt phosphorylation, with CR + INS > CON and CR at 1 h (P < 0.05) and with CR + INS + FEN > CON, CR, and CR + INS at 4 h (P < 0.05). In contrast, no changes in PKCζ/λ or GLUT4 phosphorylation were detected. CONCLUSION: Fenugreek, when combined with insulin, modulates creatine content via a mechanism which is independent of the activity of SLC6A8, suggesting that an alternative mechanism is responsible for the regulation and facilitation of insulin-mediated creatine uptake in skeletal muscle cells.
[Mh] Termos MeSH primário: Creatina/metabolismo
Hipoglicemiantes/farmacologia
Insulina/metabolismo
Fibras Musculares Esqueléticas/efeitos dos fármacos
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Sobrevivência Celular
Regulação da Expressão Gênica
Transportador de Glucose Tipo 4/genética
Transportador de Glucose Tipo 4/metabolismo
Hipoglicemiantes/química
Fibras Musculares Esqueléticas/citologia
Fibras Musculares Esqueléticas/metabolismo
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Fosfatidilinositol 3-Quinases/genética
Fosfatidilinositol 3-Quinases/metabolismo
Fosforilação
Extratos Vegetais/química
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo
Ratos
Transdução de Sinais
Trigonella/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glucose Transporter Type 4); 0 (Hypoglycemic Agents); 0 (Insulin); 0 (Nerve Tissue Proteins); 0 (Plant Extracts); 0 (Plasma Membrane Neurotransmitter Transport Proteins); 0 (Slc2a4 protein, rat); 147652-48-0 (Slc6a8 protein, rat); 68990-15-8 (fenugreek seed meal); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); MU72812GK0 (Creatine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160107
[St] Status:MEDLINE
[do] DOI:10.1007/s00394-015-1145-1


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[PMID]:27706106
[Au] Autor:Tang X; Liu H; Chen Q; Wang X; Xiong Y; Zhao P
[Ad] Endereço:State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China. 13098784616@163.com.
[Ti] Título:Genome-Wide Identification, Characterization and Expression Analysis of the Solute Carrier 6 Gene Family in Silkworm (Bombyx mori).
[So] Source:Int J Mol Sci;17(10), 2016 Oct 03.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:The solute carrier 6 (SLC6) gene family, initially known as the neurotransmitter transporters, plays vital roles in the regulation of neurotransmitter signaling, nutrient absorption and motor behavior. In this study, a total of 16 candidate genes were identified as SLC6 family gene homologs in the silkworm (Bombyx mori) genome. Spatio-temporal expression patterns of silkworm SLC6 gene transcripts indicated that these genes were highly and specifically expressed in midgut, brain and gonads; moreover, these genes were expressed primarily at the feeding stage or adult stage. Levels of expression for most midgut-specific and midgut-enriched gene transcripts were down-regulated after starvation but up-regulated after re-feeding. In addition, we observed that expression levels of these genes except for BmSLC6-15 and BmGT1 were markedly up-regulated by a juvenile hormone analog. Moreover, brain-enriched genes showed differential expression patterns during wandering and mating processes, suggesting that these genes may be involved in modulating wandering and mating behaviors. Our results improve our understanding of the expression patterns and potential physiological functions of the SLC6 gene family, and provide valuable information for the comprehensive functional analysis of the SLC6 gene family.
[Mh] Termos MeSH primário: Bombyx/genética
Bombyx/metabolismo
Regulação da Expressão Gênica
Genoma de Inseto/genética
Proteínas de Insetos/genética
Proteínas de Insetos/metabolismo
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Bombyx/classificação
Bombyx/crescimento & desenvolvimento
Encéfalo/metabolismo
Filogenia
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/classificação
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética
Alinhamento de Sequência
Comportamento Sexual Animal/fisiologia
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insect Proteins); 0 (Plasma Membrane Neurotransmitter Transport Proteins)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170330
[Lr] Data última revisão:
170330
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161006
[St] Status:MEDLINE


  8 / 232 MEDLINE  
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[PMID]:27506881
[Au] Autor:Wang J
[Ad] Endereço:Department of Pharmaceutics, University of Washington, Seattle, Washington, USA. jowang@uw.edu.
[Ti] Título:The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition.
[So] Source:Clin Pharmacol Ther;100(5):489-499, 2016 Nov.
[Is] ISSN:1532-6535
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Plasma membrane monoamine transporter (PMAT) is a new polyspecific organic cation transporter that transports a variety of biogenic amines and xenobiotic cations. Highly expressed in the brain, PMAT represents a major uptake transporter for monoamine neurotransmitters. At the blood-cerebrospinal fluid (CSF) barrier, PMAT is the principal organic cation transporter for removing neurotoxins and drugs from the CSF. Here I summarize our latest understanding of PMAT and its roles in monoamine uptake and xenobiotic disposition.
[Mh] Termos MeSH primário: Aminas Biogênicas/metabolismo
Xenobióticos/farmacocinética
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biogenic Amines); 0 (Plasma Membrane Neurotransmitter Transport Proteins); 0 (Xenobiotics)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160811
[St] Status:MEDLINE
[do] DOI:10.1002/cpt.442


  9 / 232 MEDLINE  
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[PMID]:27466184
[Au] Autor:Baroncelli L; Molinaro A; Cacciante F; Alessandrì MG; Napoli D; Putignano E; Tola J; Leuzzi V; Cioni G; Pizzorusso T
[Ad] Endereço:Institute of Neuroscience, National Research Council (CNR), Pisa, Italy baroncelli@in.cnr.it.
[Ti] Título:A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.
[So] Source:Hum Mol Genet;25(19):4186-4200, 2016 Oct 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations.
[Mh] Termos MeSH primário: Encefalopatias Metabólicas Congênitas/genética
Disfunção Cognitiva/genética
Creatina/deficiência
Deficiência Intelectual/genética
Proteínas de Membrana Transportadoras/genética
Retardo Mental Ligado ao Cromossomo X/genética
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência
[Mh] Termos MeSH secundário: Envelhecimento/genética
Envelhecimento/patologia
Animais
Encéfalo/fisiopatologia
Encefalopatias Metabólicas Congênitas/fisiopatologia
Disfunção Cognitiva/fisiopatologia
Creatina/genética
Modelos Animais de Doenças
Seres Humanos
Deficiência Intelectual/fisiopatologia
Retardo Mental Ligado ao Cromossomo X/fisiopatologia
Camundongos
Camundongos Transgênicos
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Membrane Transport Proteins); 0 (Plasma Membrane Neurotransmitter Transport Proteins); 0 (creatine transporter); MU72812GK0 (Creatine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170609
[Lr] Data última revisão:
170609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160729
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddw252


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[PMID]:27134767
[Au] Autor:He L; Pitkäniemi J; Heikkilä K; Chou YL; Madden PA; Korhonen T; Sarin AP; Ripatti S; Kaprio J; Loukola A
[Ad] Endereço:Department of Public Health University of Helsinki Helsinki Finland.
[Ti] Título:Genome-wide time-to-event analysis on smoking progression stages in a family-based study.
[So] Source:Brain Behav;6(5):e00462, 2016 May.
[Is] ISSN:2162-3279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Various pivotal stages in smoking behavior can be identified, including initiation, conversion from experimenting to established use, development of tolerance, and cessation. Previous studies have shown high heritability for age of smoking initiation and cessation; however, time-to-event genome-wide association studies aiming to identify underpinning genes that accelerate or delay these transitions are missing to date. METHODS: We investigated which single nucleotide polymorphisms (SNPs) across the whole genome contribute to the hazard ratio of transition between different stages of smoking behavior by performing time-to-event analyses within a large Finnish twin family cohort (N = 1962), and further conducted mediation analyses of plausible intermediate traits for significant SNPs. RESULTS: Genome-wide significant signals were detected for three of the four transitions: (1) for smoking cessation on 10p14 (P = 4.47e-08 for rs72779075 flanked by RP11-575N15 and GATA3), (2) for tolerance on 11p13 (P = 1.29e-08 for rs11031684 in RP1-65P5.1), mediated by smoking quantity, and on 9q34.12 (P = 3.81e-08 for rs2304808 in FUBP3), independent of smoking quantity, and (3) for smoking initiation on 19q13.33 (P = 3.37e-08 for rs73050610 flanked by TRPM4 and SLC6A16) in analysis adjusted for first time sensations. Although our top SNPs did not replicate, another SNP in the TRPM4-SLC6A16 gene region showed statistically significant association after region-based multiple testing correction in an independent Australian twin family sample. CONCLUSION: Our results suggest that the functional effect of the TRPM4-SLC6A16 gene region deserves further investigation, and that complex neurotransmitter networks including dopamine and glutamate may play a critical role in smoking initiation. Moreover, comparison of these results implies that genetic contributions to the complex smoking behavioral phenotypes vary among the transitions.
[Mh] Termos MeSH primário: Progressão da Doença
Estudo de Associação Genômica Ampla
Fumar/genética
[Mh] Termos MeSH secundário: Idoso
Austrália
Feminino
Finlândia
Seres Humanos
Masculino
Meia-Idade
Linhagem
Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética
Polimorfismo de Nucleotídeo Único
Canais de Cátion TRPM/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; TWIN STUDY
[Nm] Nome de substância:
0 (Plasma Membrane Neurotransmitter Transport Proteins); 0 (SLC6A16 protein, human); 0 (TRPM Cation Channels); 0 (TRPM4 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160503
[St] Status:MEDLINE
[do] DOI:10.1002/brb3.462



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