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Pesquisa : D12.776.157.530.400.875.750.400 [Categoria DeCS]
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[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


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[PMID]:28662944
[Au] Autor:Matthews E; Silwal A; Sud R; Hanna MG; Manzur AY; Muntoni F; Munot P
[Ad] Endereço:Medical Research Council Center for Neuromuscular Diseases, University College London and National Hospital for Neurology and Neurosurgery, London, UK. Electronic address: emma.matthews@ucl.ac.uk.
[Ti] Título:Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms.
[So] Source:J Pediatr;188:181-185.e6, 2017 Sep.
[Is] ISSN:1097-6833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To ascertain the presenting symptoms of children with skeletal muscle channelopathies to promote early diagnosis and treatment. STUDY DESIGN: Retrospective case review of 38 children with a skeletal muscle channelopathy attending the specialist pediatric neuromuscular service at Great Ormond Street Hospital over a 15-year period. RESULTS: Gait disorder and leg cramps are a frequent presentation of myotonic disorders (19 of 29). Strabismus or extraocular myotonia (9 of 19) and respiratory and/or bulbar symptoms (11 of 19) are common among those with sodium channelopathy. Neonatal hypotonia was observed in periodic paralysis. Scoliosis and/or contractures were demonstrated in 6 of 38 children. School attendance or ability to engage fully in all activities was often limited (25 of 38). CONCLUSIONS: Children with skeletal muscle channelopathies frequently display symptoms that are uncommon in adult disease. Any child presenting with abnormal gait, leg cramps, or strabismus, especially if intermittent, should prompt examination for myotonia. Those with sodium channel disease should be monitored for respiratory or bulbar complications. Neonatal hypotonia can herald periodic paralysis. Early diagnosis is essential for children to reach their full educational potential.
[Mh] Termos MeSH primário: Canalopatias/complicações
Transtornos Miotônicos/diagnóstico
Canais de Sódio/genética
[Mh] Termos MeSH secundário: Absenteísmo
Adolescente
Obstrução das Vias Respiratórias
Canalopatias/diagnóstico
Criança
Pré-Escolar
Contratura/etiologia
Diplopia/etiologia
Feminino
Transtornos Neurológicos da Marcha
Seres Humanos
Lactente
Recém-Nascido
Masculino
Cãibra Muscular/etiologia
Hipotonia Muscular/etiologia
Transtornos Miotônicos/genética
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Sons Respiratórios/etiologia
Estudos Retrospectivos
Escoliose/etiologia
Estrabismo/etiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human); 0 (Sodium Channels)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE


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[PMID]:28552867
[Au] Autor:Yamamoto J; Hokkoku K; Hatanaka Y; Sakoda S; Yuan JH; Sonoo M
[Ad] Endereço:Department of Neurology, Teikyo University School of Medicine.
[Ti] Título:An unusual case of sodium channel myotonia with transient weakness upon initiating movements which is characteristic in Becker disease.
[So] Source:Rinsho Shinkeigaku;57(6):287-292, 2017 06 28.
[Is] ISSN:1882-0654
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:We reported a 32-year-old man who was a sporadic case of myotonic syndrome with muscle stiffness or transient weakness of limbs upon initiating movements after rest. On examination, he showed painless myotonia with warm-up phenomenon, Hercules-like hypertrophic musculature and myotonic discharges in EMG. The clinical findings resembled to those of Becker disease rather than Thomsen disease. But electrodiagnosis suggested sodium channel myotonia instead of chloride channelopathy. Genetic testing detected a novel missense mutation (p.V1166A) in the SCN4A gene but not in the CLCN1 gene. Transient weakness upon initiating movements is usually observed in Becker disease but rare in Thomsen disease, which is not reported in sodium channel myotonia so far. He was probably the first case of sodium channel myotonia with transient weakness upon initiating movements, which was confirmed by 10 Hz repetitive nerve stimulation test as depolarization block.
[Mh] Termos MeSH primário: Eletrodiagnóstico
Movimento/fisiologia
Debilidade Muscular/diagnóstico
Miotonia Congênita/diagnóstico
[Mh] Termos MeSH secundário: Adulto
Eletromiografia
Testes Genéticos
Seres Humanos
Masculino
Debilidade Muscular/complicações
Debilidade Muscular/fisiopatologia
Mutação de Sentido Incorreto
Miotonia Congênita/complicações
Miotonia Congênita/genética
Miotonia Congênita/patologia
Miotonia Congênita/fisiopatologia
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Estimulação Elétrica Nervosa Transcutânea
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE
[do] DOI:10.5692/clinicalneurol.cn-000980


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[PMID]:28330959
[Au] Autor:Palmio J; Sandell S; Hanna MG; Männikkö R; Penttilä S; Udd B
[Ad] Endereço:From the Neuromuscular Research Center (J.P., S.P., B.U.), Department of Neurology, Tampere University and University Hospital, Neurology; Seinäjoki Central Hospital (S.S.), Department of Neurology, Finland; MRC Centre for Neuromuscular Disease (M.G.H., R.M.), UCL Institute of Neurology, Queen Squar
[Ti] Título:Predominantly myalgic phenotype caused by the c.3466G>A p.A1156T mutation in gene.
[So] Source:Neurology;88(16):1520-1527, 2017 Apr 18.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation. METHODS: Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in the gene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p.A1156T mutation were studied in HEK293 cells with whole-cell patch clamp. RESULTS: The main clinical manifestation in p.A1156T patients was not myotonia or periodic paralysis but exercise- and cold-induced muscle cramps, muscle stiffness, and myalgia. EMG myotonic discharges were detected in most but not all. Electrophysiologic compound muscle action potentials exercise test showed variable results. The p.A1156T mutation was identified in one patient in the DM2-neg group but not in the fibromyalgia group, making a total of 30 patients so far identified. Functional studies of the p.A1156T mutation showed mild attenuation of channel fast inactivation. CONCLUSIONS: The unspecific symptoms of myalgia stiffness and exercise intolerance without clinical myotonia or periodic paralysis in p.A1156T patients make the diagnosis challenging. The symptoms of milder mutations may be confused with other similar myalgic syndromes, including fibromyalgia and myotonic dystrophy type 2.
[Mh] Termos MeSH primário: Mutação
Mialgia/genética
Mialgia/fisiopatologia
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Estudos de Coortes
Análise Mutacional de DNA
Grupo com Ancestrais do Continente Europeu/genética
Família
Feminino
Fibromialgia/genética
Fibromialgia/fisiopatologia
Finlândia
Células HEK293
Seres Humanos
Masculino
Meia-Idade
Distrofia Miotônica/genética
Distrofia Miotônica/fisiopatologia
Técnicas de Patch-Clamp
Fenótipo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000003846


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[PMID]:28057491
[Au] Autor:Paiz-Candia B; Islas AA; Sánchez-Solano A; Mancilla-Simbro C; Scior T; Millan-PerezPeña L; Salinas-Stefanon EM
[Ad] Endereço:Facultad de Ciencias Químicas, Universidad Autónoma de Puebla, 14 Sur 6301, CU, San Manuel, Puebla, México. Electronic address: bertin.paiz@gmail.com.
[Ti] Título:Mefloquine inhibits voltage dependent Na 1.4 channel by overlapping the local anaesthetic binding site.
[So] Source:Eur J Pharmacol;796:215-223, 2017 Feb 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mefloquine constitutes a multitarget antimalaric that inhibits cation currents. However, the effect and the binding site of this compound on Na channels is unknown. To address the mechanism of action of mefloquine, we employed two-electrode voltage clamp recordings on Xenopus laevis oocytes, site-directed mutagenesis of the rat Na channel, and a combined in silico approach using Molecular Dynamics and docking protocols. We found that mefloquine: i) inhibited Na 1.4 currents (IC =60µM), ii) significantly delayed fast inactivation but did not affect recovery from inactivation, iii) markedly the shifted steady-state inactivation curve to more hyperpolarized potentials. The presence of the ß1 subunit significantly reduced mefloquine potency, but the drug induced a significant frequency-independent rundown upon repetitive depolarisations. Computational and experimental results indicate that mefloquine overlaps the local anaesthetic binding site by docking at a hydrophobic cavity between domains DIII and DIV that communicates the local anaesthetic binding site with the selectivity filter. This is supported by the fact that mefloquine potency significantly decreased on mutant Na 1.4 channel F1579A and significantly increased on K1237S channels. In silico this compound docked above F1579 forming stable π-π interactions with this residue. We provide structure-activity insights into how cationic amphiphilic compounds may exert inhibitory effects by docking between the local anaesthetic binding site and the selectivity filter of a mammalian Na channel. Our proposed synergistic cycle of experimental and computational studies may be useful for elucidating binding sites of other drugs, thereby saving in vitro and in silico resources.
[Mh] Termos MeSH primário: Anestésicos Locais/metabolismo
Anestésicos Locais/farmacologia
Mefloquina/metabolismo
Mefloquina/farmacologia
Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo
Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Relação Dose-Resposta a Droga
Fenômenos Eletrofisiológicos/efeitos dos fármacos
Lidocaína/metabolismo
Lidocaína/farmacologia
Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Mutagênese Sítio-Dirigida
Canal de Sódio Disparado por Voltagem NAV1.4/química
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Conformação Proteica
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics, Local); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (Voltage-Gated Sodium Channel Blockers); 98PI200987 (Lidocaine); TML814419R (Mefloquine)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE


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[PMID]:28034736
[Au] Autor:Del Río-Sancho S; Cros C; Coutaz B; Cuendet M; Kalia YN
[Ad] Endereço:School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, 1 Rue Michel-Servet, 1211 Geneva, Switzerland.
[Ti] Título:Cutaneous iontophoresis of µ-conotoxin CnIIIC-A potent Na 1.4 antagonist with analgesic, anaesthetic and myorelaxant properties.
[So] Source:Int J Pharm;518(1-2):59-65, 2017 Feb 25.
[Is] ISSN:1873-3476
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cutaneous iontophoretic delivery of µ-conotoxin CnIIIC (XEP), a potent peptide antagonist of the Na 1.4 sodium channel, was investigated using porcine ear skin and validated using human abdominal skin. Initial results demonstrated that cutaneous deposition of XEP following iontophoresis was superior to passive delivery and increased with current density. XEP deposition after iontophoresis at 0.1, 0.3 and 0.5mA/cm for 2h and 4h was 22.4±0.4, 34.5±1.4, 57.4±7.6µg/cm and 30.6±5.4, 53.9±17.2, 90.9±30.8µg/cm , respectively (cf. corresponding passive controls - 9.8±1.1 and 16.9±1.0µg/cm ). Moreover, tape-stripping studies showed that XEP was mainly adsorbed on the skin surface when administered passively. Co-iontophoresis of acetaminophen demonstrated that XEP was present in the skin as it significantly reduced convective solvent flow as evidenced by the ∼7-fold decrease in acetaminophen permeation. Shorter duration iontophoresis (15, 30 and 60min) was performed and the effect of current density (0.1, 0.3 and 0.5mA/cm ) and concentration (0.1 and 1mM) investigated. Skin deposition of XEP was already quantifiable after iontophoresis for 15min at the lower concentration. There was no statistically significant difference between XEP deposition in porcine and human skin. Confocal laser scanning microscopy enabled post-iontophoretic visualization of FITC-labelled XEP in the epidermis.
[Mh] Termos MeSH primário: Conotoxinas/administração & dosagem
Pele/metabolismo
Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem
[Mh] Termos MeSH secundário: Administração Cutânea
Analgésicos/administração & dosagem
Analgésicos/farmacocinética
Anestésicos/administração & dosagem
Anestésicos/farmacocinética
Animais
Conotoxinas/farmacocinética
Seres Humanos
Iontoforese
Canal de Sódio Disparado por Voltagem NAV1.4
Fármacos Neuromusculares/administração & dosagem
Fármacos Neuromusculares/farmacocinética
Reprodutibilidade dos Testes
Absorção Cutânea
Suínos
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Anesthetics); 0 (Conotoxins); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (Neuromuscular Agents); 0 (Voltage-Gated Sodium Channel Blockers)
[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:161231
[St] Status:MEDLINE


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[PMID]:28012096
[Au] Autor:Benhammou JN; Phan J; Lee H; Ghassemi K; Parsons W; Grody WW; Pisegna JR
[Ad] Endereço:Division of Digestive Diseases, Department of Medicine, and Departments of Pathology & Laboratory Medicine and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
[Ti] Título:A Sodium Channel Myotonia Presenting with Intermittent Dysphagia as a Manifestation of a Rare SCN4A Variant.
[So] Source:J Mol Neurosci;61(3):312-314, 2017 Mar.
[Is] ISSN:1559-1166
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The voltage gated sodium channel SCN4A mutations account for non-dystrophic myotonia and include a heterogeneous group of conditions that include hyperkalemic periodic paralysis, paramyotonica congenita, potassium-aggravated myotonia, and hypokalemic periodic paralysis type 2. This case report proposes that a rare variant p.Pro1629Leu in SCN4A can cause a skeletal muscle deficit with intermittent dysphagia.
[Mh] Termos MeSH primário: Transtornos de Deglutição/genética
Mutação de Sentido Incorreto
Miotonia/genética
Canal de Sódio Disparado por Voltagem NAV1.4/genética
[Mh] Termos MeSH secundário: Transtornos de Deglutição/diagnóstico
Feminino
Seres Humanos
Meia-Idade
Músculo Esquelético/metabolismo
Músculo Esquelético/fisiopatologia
Miotonia/diagnóstico
Potássio/metabolismo
Síndrome
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human); RWP5GA015D (Potassium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161225
[St] Status:MEDLINE
[do] DOI:10.1007/s12031-016-0878-5


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[PMID]:28012039
[Au] Autor:Sánchez-Solano A; Islas AA; Scior T; Paiz-Candia B; Millan-PerezPeña L; Salinas-Stefanon EM
[Ad] Endereço:Laboratorio de Biofísica, Instituto de Fisiología, Universidad Autónoma de Puebla, 14 Sur No. 6301 C.U., 72570, Puebla, Pue, Mexico.
[Ti] Título:Characterization of specific allosteric effects of the Na channel ß1 subunit on the Na 1.4 isoform.
[So] Source:Eur Biophys J;46(5):485-494, 2017 Jul.
[Is] ISSN:1432-1017
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The mechanism of inactivation of mammalian voltage-gated Na channels involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the ß1 subunit. Na ß1 subunits constitute single-pass transmembrane proteins that form protein-protein associations with pore-forming α subunits to allosterically modulate the Na influx into the cell during the action potential of every excitable cell in vertebrates. Here, we explored the role of the intracellular IFM motif of rNa 1.4 (skeletal muscle isoform of the rat Na channel) on the α-ß1 functional interaction and showed for the first time that the modulation of ß1 is independent of the IFM motif. We found that: (1) Na 1.4 channels that lack the IFM inactivation particle can undergo a "C-type-like inactivation" albeit in an ultraslow gating mode; (2) ß1 can significantly accelerate the inactivation of Na 1.4 channels in the absence of the IFM motif. Previously, we identified two residues (T109 and N110) on the ß1 subunit that disrupt the α-ß1 allosteric modulation. We further characterized the electrophysiological effects of the double alanine substitution of these residues demonstrating that it decelerates inactivation and recovery from inactivation, abolishes the modulation of steady-state inactivation and induces a current rundown upon repetitive stimulation, thus causing a general loss of function. Our results contribute to delineating the process of the mammalian Na channel inactivation. These findings may be relevant to the design of pharmacological strategies, targeting ß subunits to treat pathologies associated to Na current dysfunction.
[Mh] Termos MeSH primário: Canal de Sódio Disparado por Voltagem NAV1.4/química
Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/química
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica
Motivos de Aminoácidos
Animais
Fenômenos Eletrofisiológicos
Espaço Intracelular/metabolismo
Cinética
Modelos Moleculares
Mutação
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (Voltage-Gated Sodium Channel beta-1 Subunit)
[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:161225
[St] Status:MEDLINE
[do] DOI:10.1007/s00249-016-1193-3


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[PMID]:27743929
[Au] Autor:De Bellis M; Carbonara R; Roussel J; Farinato A; Massari A; Pierno S; Muraglia M; Corbo F; Franchini C; Carratù MR; De Luca A; Conte Camerino D; Desaphy JF
[Ad] Endereço:Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari Aldo Moro, 70125, Bari, Italy.
[Ti] Título:Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity.
[So] Source:Neuropharmacology;113(Pt A):206-216, 2017 Feb.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers. The current study was performed to verify their potential as antimyotonic agents. Patch-clamp experiments show that both compounds, especially To042, are greatly more potent and use-dependent blockers of human skeletal muscle hNav1.4 channels compared to tocainide and mexiletine. Reduced effects on F1586C hNav1.4 mutant suggest that the compounds bind to the local anesthetic receptor, but that the increased hindrance and lipophilia of the N-substituent may further strengthen drug-receptor interaction and use-dependence. Compared to mexiletine, To042 was 120 times more potent to block hNav1.4 channels in a myotonia-like cellular condition and 100 times more potent to improve muscle stiffness in vivo in a previously-validated rat model of myotonia. To explore toxicological profile, To042 was tested on hERG potassium currents, motor coordination using rotarod, and C2C12 cell line for cytotoxicity. All these experiments suggest a satisfactory therapeutic index for To042. This study shows that, owing to a huge use-dependent block of sodium channels, To042 is a promising candidate drug for myotonia and possibly other membrane excitability disorders, warranting further preclinical and human studies.
[Mh] Termos MeSH primário: Miotonia/prevenção & controle
Canal de Sódio Disparado por Voltagem NAV1.4/fisiologia
Tocainide/farmacologia
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Canais de Potássio Éter-A-Go-Go/fisiologia
Seres Humanos
Masculino
Mexiletina/farmacologia
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/fisiologia
Miotonia/fisiopatologia
Ratos
Ratos Wistar
Reflexo de Endireitamento/efeitos dos fármacos
Teste de Desempenho do Rota-Rod
Tocainide/efeitos adversos
Tocainide/análogos & derivados
Tocainide/uso terapêutico
Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos
Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ether-A-Go-Go Potassium Channels); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human); 0 (Voltage-Gated Sodium Channel Blockers); 1U511HHV4Z (Mexiletine); 27DXO59SAN (Tocainide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:27415035
[Au] Autor:Yang X; Jia H; An R; Xi J; Xu Y
[Ad] Endereço:a Department of Neurology , West China Hospital, Sichuan University , Chengdu , Sichuan Province , P.R. China.
[Ti] Título:Sequence CLCN1 and SCN4A in patients with Nondystrophic myotonias in Chinese populations: Genetic and pedigree analysis of 10 families and review of the literature.
[So] Source:Channels (Austin);11(1):55-65, 2017 Jan 02.
[Is] ISSN:1933-6969
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Myotonia congenita (MC), paramyotonia congenita (PC) and sodium channel myotonias(SCM) were belonged to Non-dystrophic myotonias, in which muscle relaxation is delayed after voluntary or evoked contraction. These diseases can not be simply distinguished only based on symptoms and signs but also on genetics: more than 100 mutations in the CLCN1 gene have been associated with MC, while at least 20 mutations in the SCN4A gene have been associated with PC and SCM. Most of these genetics studies have been conducted outside China, only several MC, PC, and SCM families accepted gene scan were reported in China. Therefore we analyzed genetic mutations in CLCN1 and SCN4A in 10 Chinese families clinically diagnosed with Non-dystrophic myotonias. Our result revealed 12 potential disease-causing mutations(3 mutations were novel) that were present in the probands and affected family members. We also reviewed all available literature on mutations linked to these 3 disease in Chinese populations. Our results may help identify genetic determinants as well as clarify genotype-phenotype relationships.
[Mh] Termos MeSH primário: Canais de Cloreto/genética
Miotonia/genética
Canal de Sódio Disparado por Voltagem NAV1.4/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Grupo com Ancestrais do Continente Asiático/genética
Seres Humanos
Masculino
Mutação
Linhagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CLC-1 channel); 0 (Chloride Channels); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160715
[St] Status:MEDLINE
[do] DOI:10.1080/19336950.2016.1212140



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