Base de dados : MEDLINE
Pesquisa : D12.776.157.530.400.875.750.600 [Categoria DeCS]
Referências encontradas : 283 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 29 ir para página                         

  1 / 283 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29258861
[Au] Autor:Carcamo-Noriega EN; Olamendi-Portugal T; Restano-Cassulini R; Rowe A; Uribe-Romero SJ; Becerril B; Possani LD
[Ad] Endereço:Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, UNAM, Av. Universidad 2001, Apartado Postal 510-3, Cuernavaca, Morelos 62210, Mexico. Electronic address: edsoncar@ibt.unam.mx.
[Ti] Título:Intraspecific variation of Centruroides sculpturatus scorpion venom from two regions of Arizona.
[So] Source:Arch Biochem Biophys;638:52-57, 2018 01 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This study investigated geographic variability in the venom of Centruroides sculpturatus scorpions from different biotopes. Venom from scorpions collected from two different regions in Arizona; Santa Rita Foothills (SR) and Yarnell (Yar) were analyzed. We found differences between venoms, mainly in the two most abundant peptides; SR (CsEv2e and CsEv1f) and Yar (CsEv2 and CsEv1c) identified as natural variants of CsEv1 and CsEv2. Sequence analyses of these peptides revealed conservative amino acid changes between variants, which may underlie biological activity against arthropods. A third peptide (CsEv6) was highly abundant in the Yar venom compared to the SR venom. CsEv6 is a 67 amino acid peptide with 8 cysteines. CsEv6 did not exhibit toxicity to the three animal models tested. However, both venoms shared similarities in peptides that are predicted to deter predators. For example, both venoms expressed CsEI (lethal to chick) in similar abundance, while CsEd and CsEM1a (toxic to mammals) displayed only moderate variation in their abundance. Electrophysiological evaluation of CsEd and CsEM1a showed that both toxins act on the human sodium-channel subtype 1.6 (hNav 1.6). Complete sequencing revealed that both toxins are structurally similar to beta-toxins isolated from different Centruroides species that also target hNav 1.6.
[Mh] Termos MeSH primário: Proteínas de Artrópodes
Variação Genética
Venenos de Escorpião
Escorpiões
[Mh] Termos MeSH secundário: Animais
Arizona
Proteínas de Artrópodes/química
Proteínas de Artrópodes/genética
Proteínas de Artrópodes/toxicidade
Células CHO
Galinhas
Cricetulus
Gryllidae
Células HEK293
Seres Humanos
Camundongos
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo
Venenos de Escorpião/química
Venenos de Escorpião/genética
Venenos de Escorpião/toxicidade
Escorpiões/química
Escorpiões/genética
Análise de Sequência de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Arthropod Proteins); 0 (Centruroides toxin); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (SCN8A protein, human); 0 (Scorpion Venoms); 141322-33-0 (toxin 2, Centruroides noxius)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE


  2 / 283 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28923014
[Au] Autor:Wang J; Gao H; Bao X; Zhang Q; Li J; Wei L; Wu X; Chen Y; Yu S
[Ad] Endereço:Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.
[Ti] Título:SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures.
[So] Source:BMC Med Genet;18(1):104, 2017 Sep 18.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations. METHODS: To identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained. RESULTS: A heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence. CONCLUSIONS: Our findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.
[Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética
Mutação de Sentido Incorreto
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Convulsões/genética
Espasmos Infantis/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Sequência de Aminoácidos
Criança
Pré-Escolar
Morte Súbita
Feminino
Heterozigoto
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Lactente
Meia-Idade
Linhagem
Análise de Sequência de DNA
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (SCN8A protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0460-1


  3 / 283 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28880996
[Au] Autor:Steel D; Symonds JD; Zuberi SM; Brunklaus A
[Ad] Endereço:The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom.
[Ti] Título:Dravet syndrome and its mimics: Beyond SCN1A.
[So] Source:Epilepsia;58(11):1807-1816, 2017 Nov.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non-SCN1A genes in DS, and what is known about phenotypic similarities and differences. We discuss whether these are best thought of as minority causes of DS, or as similar but distinct conditions. METHODS: Based on a review of literature, a list of genes linked to DS was compiled and PubMed was searched for reports of DS-like phenotypes arising from variants in each. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. RESULTS: Genes that have been reported to cause DS-like phenotypes include SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2. Many of these genes, however, appear to be associated with their own, different, clinical picture. Other candidate genes for DS have been reported, but there is currently an insufficient body of literature to support their causative role. SIGNIFICANCE: Although most cases of DS arise from SCN1A variants, numerous other genes cause encephalopathies that are clinically similar. Increasingly, a tendency is noted to define newly described epileptic disorders primarily in genetic terms, with clinical features being linked to genotypes. As genetic diagnosis becomes more readily available, its potential to guide pathophysiologic understanding and therapeutic strategy cannot be ignored. Clinical assessment remains essential; the challenge now is to develop a gene-based taxonomy that complements traditional syndromic classifications, allowing elements of both to inform new approaches to treatment.
[Mh] Termos MeSH primário: Epilepsias Mioclônicas/diagnóstico
Epilepsias Mioclônicas/genética
Mutação/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
[Mh] Termos MeSH secundário: Seres Humanos
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Fenótipo
Receptores de GABA-A/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GABRA1 protein, human); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (Receptors, GABA-A); 0 (SCN1A protein, human); 0 (SCN2A protein, human); 0 (SCN8A protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13889


  4 / 283 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28683073
[Au] Autor:Li T; Lu G; Chiang EY; Chernov-Rogan T; Grogan JL; Chen J
[Ad] Endereço:Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, California, United States of America.
[Ti] Título:High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE.
[So] Source:PLoS One;12(7):e0180154, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ion channels regulate a variety of physiological processes and represent an important class of drug target. Among the many methods of studying ion channel function, patch clamp electrophysiology is considered the gold standard by providing the ultimate precision and flexibility. However, its utility in ion channel drug discovery is impeded by low throughput. Additionally, characterization of endogenous ion channels in primary cells remains technical challenging. In recent years, many automated patch clamp (APC) platforms have been developed to overcome these challenges, albeit with varying throughput, data quality and success rate. In this study, we utilized SyncroPatch 768PE, one of the latest generation APC platforms which conducts parallel recording from two-384 modules with giga-seal data quality, to push these 2 boundaries. By optimizing various cell patching parameters and a two-step voltage protocol, we developed a high throughput APC assay for the voltage-gated sodium channel Nav1.7. By testing a group of Nav1.7 reference compounds' IC50, this assay was proved to be highly consistent with manual patch clamp (R > 0.9). In a pilot screening of 10,000 compounds, the success rate, defined by > 500 MΩ seal resistance and >500 pA peak current, was 79%. The assay was robust with daily throughput ~ 6,000 data points and Z' factor 0.72. Using the same platform, we also successfully recorded endogenous voltage-gated potassium channel Kv1.3 in primary T cells. Together, our data suggest that SyncroPatch 768PE provides a powerful platform for ion channel research and drug discovery.
[Mh] Termos MeSH primário: Ensaios de Triagem em Larga Escala/métodos
Potenciais da Membrana/fisiologia
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Técnicas de Patch-Clamp/métodos
Bloqueadores dos Canais de Potássio/farmacologia
Bloqueadores dos Canais de Sódio/farmacologia
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetulus
Avaliação Pré-Clínica de Medicamentos
Expressão Gênica
Ensaios de Triagem em Larga Escala/instrumentação
Canal de Potássio Kv1.3/deficiência
Canal de Potássio Kv1.3/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.3/genética
Canal de Sódio Disparado por Voltagem NAV1.3/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.5/genética
Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.7/genética
Técnicas de Patch-Clamp/instrumentação
Cultura Primária de Células
Ratos
Canais de Sódio/genética
Canais de Sódio/metabolismo
Linfócitos T/citologia
Linfócitos T/efeitos dos fármacos
Linfócitos T/metabolismo
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Kv1.3 Potassium Channel); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.3 Voltage-Gated Sodium Channel); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (NAV1.5 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (Potassium Channel Blockers); 0 (SCN1A protein, human); 0 (SCN3A protein, human); 0 (SCN4A protein, human); 0 (SCN5A protein, human); 0 (SCN8A protein, human); 0 (SCN9A protein, human); 0 (Sodium Channel Blockers); 0 (Sodium Channels)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180154


  5 / 283 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28676574
[Au] Autor:Ottolini M; Barker BS; Gaykema RP; Meisler MH; Patel MK
[Ad] Endereço:Department of Anesthesiology and.
[Ti] Título:Aberrant Sodium Channel Currents and Hyperexcitability of Medial Entorhinal Cortex Neurons in a Mouse Model of Encephalopathy.
[So] Source:J Neurosci;37(32):7643-7655, 2017 Aug 09.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:encephalopathy, or early infantile epileptic encephalopathy 13 (EIEE13), is caused predominantly by gain-of-function mutations in the voltage-gated Na channel Na 1.6. Affected individuals suffer from refractory seizures, developmental delay, cognitive disability, and elevated risk of sudden unexpected death in epilepsy (SUDEP). A knock-in mouse model carrying the patient mutation p.Asn1768Asp (N1768D) reproduces many features of the disorder, including spontaneous seizures and SUDEP. We used the mouse model to examine the effects of the mutation on layer II stellate neurons of the medial entorhinal cortex (mEC), which transmit excitatory input to the hippocampus. Heterozygous ( ), homozygous ( ), and WT ( ) littermates were compared at 3 weeks of age, the time of seizure onset for homozygous mice. Heterozygotes remain seizure free for another month. mEC layer II neurons of heterozygous and homozygous mice were hyperexcitable and generated long-lasting depolarizing potentials with bursts of action potentials after synaptic stimulation. Recording of Na currents revealed proexcitatory increases in persistent and resurgent currents and rightward shifts in inactivation parameters, leading to significant increases in the magnitude of window currents. The proexcitatory changes were more pronounced in homozygous mice than in heterozygotes, consistent with the earlier age of seizure onset in homozygotes. These studies demonstrate that the N1768D mutation increases the excitability of mEC layer II neurons by increasing persistent and resurgent Na currents and disrupting channel inactivation. The aberrant activities of mEC layer II neurons would provide excessive excitatory input to the hippocampus and contribute to hyperexcitability of hippocampal neurons in this model of encephalopathy. encephalopathy is a devastating neurological disorder that results from mutations in the Na channel Na 1.6. In addition to seizures, patients suffer from cognitive and developmental delays and are at high risk for sudden unexpected death in epilepsy (SUDEP). A mouse knock-in model expressing the patient mutation N1768D reproduces several pathological phenotypes, including spontaneous seizures and sudden death. We demonstrate that medial entorhinal cortex (mEC) neurons from the mouse model exhibit proexcitatory alterations in Na channel activity, some of which were not seen in hippocampal or cortical neurons, and resulting in neuronal hyperexcitability. Because mEC neurons regulate the activity of the hippocampus, which plays an important role in seizure onset, we propose that these profound changes in mEC neuron excitability associated with the gain-of-function mutation of Na 1.6 may increase excitatory drive into the hippocampus, culminating in seizure activity and SUDEP.
[Mh] Termos MeSH primário: Encefalopatias/genética
Encefalopatias/fisiopatologia
Modelos Animais de Doenças
Córtex Entorrinal/fisiopatologia
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Neurônios/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação/fisiologia
Animais
Síndrome de Brugada/genética
Síndrome de Brugada/fisiopatologia
Epilepsia/genética
Epilepsia/fisiopatologia
Feminino
Técnicas de Introdução de Genes/métodos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Mutação/genética
Técnicas de Cultura de Órgãos
Canais de Sódio/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (Scn8a protein, mouse); 0 (Sodium Channels)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170706
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.2709-16.2017


  6 / 283 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28518218
[Au] Autor:Holland KD; Bouley TM; Horn PS
[Ad] Endereço:Departments of Pediatrics and Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
[Ti] Título:Comparison and optimization of in silico algorithms for predicting the pathogenicity of sodium channel variants in epilepsy.
[So] Source:Epilepsia;58(7):1190-1198, 2017 Jul.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians' understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel (SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy. METHODS: Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity. RESULTS: Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52-0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm had an accuracy of 0.90 and a combination of algorithms increased the accuracy to 0.92. SIGNIFICANCE: Potentially pathogenic variants are present in population-based sources. Most computational algorithms overestimate pathogenicity; however, a weighted combination of several algorithms increased classification accuracy to >0.90.
[Mh] Termos MeSH primário: Algoritmos
Simulação por Computador
Epilepsia/genética
Epilepsia/fisiopatologia
Variação Genética/genética
Mutação de Sentido Incorreto/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Canais de Sódio/genética
[Mh] Termos MeSH secundário: Análise Mutacional de DNA
Bases de Dados Genéticas
Predisposição Genética para Doença/genética
Seres Humanos
Lactente
Fenótipo
Valor Preditivo dos Testes
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human); 0 (SCN2A protein, human); 0 (SCN8A protein, human); 0 (Sodium Channels)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13798


  7 / 283 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28238546
[Au] Autor:Makinson CD; Tanaka BS; Sorokin JM; Wong JC; Christian CA; Goldin AL; Escayg A; Huguenard JR
[Ad] Endereço:Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94304, USA.
[Ti] Título:Regulation of Thalamic and Cortical Network Synchrony by Scn8a.
[So] Source:Neuron;93(5):1165-1179.e6, 2017 Mar 08.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Voltage-gated sodium channel (VGSC) mutations cause severe epilepsies marked by intermittent, pathological hypersynchronous brain states. Here we present two mechanisms that help to explain how mutations in one VGSC gene, Scn8a, contribute to two distinct seizure phenotypes: (1) hypoexcitation of cortical circuits leading to convulsive seizure resistance, and (2) hyperexcitation of thalamocortical circuits leading to non-convulsive absence epilepsy. We found that loss of Scn8a leads to altered RT cell intrinsic excitability and a failure in recurrent RT synaptic inhibition. We propose that these deficits cooperate to enhance thalamocortical network synchrony and generate pathological oscillations. To our knowledge, this finding is the first clear demonstration of a pathological state tied to disruption of the RT-RT synapse. Our observation that loss of a single gene in the thalamus of an adult wild-type animal is sufficient to cause spike-wave discharges is striking and represents an example of absence epilepsy of thalamic origin.
[Mh] Termos MeSH primário: Canal de Sódio Disparado por Voltagem NAV1.6/genética
Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo
Rede Nervosa/metabolismo
Sinapses/metabolismo
Tálamo/metabolismo
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Eletroencefalografia/métodos
Epilepsia Tipo Ausência/genética
Epilepsia Tipo Ausência/metabolismo
Camundongos
Fenótipo
Convulsões/genética
Convulsões/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (Scn8a protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170228
[St] Status:MEDLINE


  8 / 283 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28079757
[Au] Autor:Lin YM; Fu Y; Winston J; Radhakrishnan R; Sarna SK; Huang LM; Shi XZ
[Ad] Endereço:Departments of aInternal Medicine bSurgery and cNeuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
[Ti] Título:Pathogenesis of abdominal pain in bowel obstruction: role of mechanical stress-induced upregulation of nerve growth factor in gut smooth muscle cells.
[So] Source:Pain;158(4):583-592, 2017 Apr.
[Is] ISSN:1872-6623
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Abdominal pain is one of the major symptoms in bowel obstruction (BO); its cellular mechanisms remain incompletely understood. We tested the hypothesis that mechanical stress in obstruction upregulates expression of nociception mediator nerve growth factor (NGF) in gut smooth muscle cells (SMCs), and NGF sensitizes primary sensory nerve to contribute to pain in BO. Partial colon obstruction was induced with a silicon band implanted in the distal bowel of Sprague-Dawley rats. Colon-projecting sensory neurons in the dorsal root ganglia (T13 to L2) were identified for patch-clamp and gene expression studies. Referred visceral sensitivity was assessed by measuring withdrawal response to stimulation by von Frey filaments in the lower abdomen. Membrane excitability of colon-projecting dorsal root ganglia neurons was significantly enhanced, and the withdrawal response to von Frey filament stimulation markedly increased in BO rats. The expression of NGF mRNA and protein was increased in a time-dependent manner (day 1-day 7) in colonic SMC but not in mucosa/submucosa of the obstructed colon. Mechanical stretch in vitro caused robust NGF mRNA and protein expression in colonic SMC. Treatment with anti-NGF antibody attenuated colon neuron hyperexcitability and referred hypersensitivity in BO rats. Obstruction led to significant increases of tetrodotoxin-resistant Na currents and mRNA expression of Nav1.8 but not Nav1.6 and Nav1.7 in colon neurons; these changes were abolished by anti-NGF treatment. In conclusion, mechanical stress-induced upregulation of NGF in colon SMC underlies the visceral hypersensitivity in BO through increased gene expression and activity of tetrodotoxin-resistant Na channels in sensory neurons.
[Mh] Termos MeSH primário: Colo/patologia
Miócitos de Músculo Liso/metabolismo
Fator de Crescimento Neural/metabolismo
Células Receptoras Sensoriais/metabolismo
Regulação para Cima/fisiologia
[Mh] Termos MeSH secundário: Animais
Anticorpos/uso terapêutico
Doença de Bowen/tratamento farmacológico
Doença de Bowen/etiologia
Doença de Bowen/patologia
Células Cultivadas
Colo/inervação
Modelos Animais de Doenças
Gânglios Espinais/patologia
Masculino
Potenciais da Membrana/efeitos dos fármacos
Potenciais da Membrana/fisiologia
Miócitos de Músculo Liso/patologia
Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Fator de Crescimento Neural/genética
Fator de Crescimento Neural/imunologia
Técnicas de Patch-Clamp
Ratos
Ratos Sprague-Dawley
Bloqueadores dos Canais de Sódio/farmacologia
Tetrodotoxina/farmacologia
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (Scn8a protein, rat); 0 (Scn9a protein, rat); 0 (Sodium Channel Blockers); 4368-28-9 (Tetrodotoxin); 9061-61-4 (Nerve Growth Factor)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170113
[St] Status:MEDLINE
[do] DOI:10.1097/j.pain.0000000000000797


  9 / 283 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27999940
[Au] Autor:Barbosa C; Xiao Y; Johnson AJ; Xie W; Strong JA; Zhang JM; Cummins TR
[Ad] Endereço:Department of Pharmacology and Toxicology, Indiana University, Indianapolis, IN, USA.
[Ti] Título:FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons.
[So] Source:Pflugers Arch;469(2):195-212, 2017 Feb.
[Is] ISSN:1432-2013
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6-mediated resurgent currents by isoforms of fibroblast growth factor homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas FHF2B enhances resurgent currents. Overall, our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast, FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navß4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents, suggesting that specific regions within FHF2A and Navß4 have important regulatory functions. Our data also indicate that FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies.
[Mh] Termos MeSH primário: Fatores de Crescimento de Fibroblastos/metabolismo
Gânglios Espinais/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo
Isoformas de Proteínas/metabolismo
Sódio/metabolismo
[Mh] Termos MeSH secundário: Potenciais de Ação/fisiologia
Animais
Ativação do Canal Iônico/fisiologia
Masculino
Ratos
Ratos Sprague-Dawley
Células Receptoras Sensoriais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FHF2B protein, rat); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (Protein Isoforms); 62031-54-3 (Fibroblast Growth Factors); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1007/s00424-016-1911-9


  10 / 283 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27836728
[Au] Autor:Sprissler RS; Wagnon JL; Bunton-Stasyshyn RK; Meisler MH; Hammer MF
[Ad] Endereço:ARL Division of Biotechnology, University of Arizona, Tucson, AZ 85721, USA.
[Ti] Título:Altered gene expression profile in a mouse model of SCN8A encephalopathy.
[So] Source:Exp Neurol;288:134-141, 2017 Feb.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Na 1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3-fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.
[Mh] Termos MeSH primário: Encefalopatias
Epilepsia
Regulação da Expressão Gênica/genética
Canal de Sódio Disparado por Voltagem NAV1.6/deficiência
Transcriptoma/genética
[Mh] Termos MeSH secundário: Animais
Encefalopatias/complicações
Encefalopatias/genética
Encefalopatias/metabolismo
Modelos Animais de Doenças
Epilepsia/etiologia
Epilepsia/genética
Epilepsia/metabolismo
Camundongos
Camundongos Transgênicos
Mutação/genética
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Neuropeptídeos/metabolismo
Análise de Componente Principal
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (Neuropeptides); 0 (Scn8a protein, mouse)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161113
[St] Status:MEDLINE



página 1 de 29 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde