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Pesquisa : D12.776.157.530.400.600 [Categoria DeCS]
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[PMID]:29212069
[Au] Autor:Eckert M; Klumpp L; Huber SM
[Ad] Endereço:Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.
[Ti] Título:Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma.
[So] Source:Cell Physiol Biochem;44(4):1591-1605, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug is used to treat epileptic seizure of glioblastoma patients. Besides its antiepileptic activity, VPA has been attributed further functions that improve the clinical outcome of glioblastoma patients. Those comprise the inhibition of some histone deacetylase (HDAC) isoforms which reportedly may result in radiosensitization. Retrospective analysis of patient data, however, could not unequivocally confirm a prolonged survival of glioblastoma patients receiving VPA. The present study aimed to identify potential VPA targets at the cellular level. METHODS: To this end, the effect of VPA on metabolism, Ca2+-, biochemical and electro-signaling, cell-cycling, clonogenic survival and transfilter migration was analyzed in three human glioblastoma lines (T98G, U-87MG, U251) by MTT assay, Ca2+ imaging, immunoblotting, patch-clamp recording, flow cytometry, delayed plating colony formation and modified Boyden chamber assays, respectively. In addition, the effect of VPA on clonogenic survival of primary glioblastoma spheroid cultures treated with temozolomide and fractionated radiation was assessed by limited dilution assay. RESULTS: In 2 of 3 glioblastoma lines, clinical relevant concentrations of VPA slightly slowed down cell cycle progression and decreased clonogenic survival. Furthermore, VPA induced Ca2+ signaling which was accompanied by pronounced K+ channel activity and transfilter cell migration. VPA did not affect metabolic NAD(P)H formation or radioresistance of the glioblastoma lines. Finally, VPA did not impair clonogenic survival or radioresistance of temozolomide-treated primary spheroid cultures. CONCLUSIONS: Combined, our in vitro data do not propose a general use of VPA as a radiosensitizer in anti-glioblastoma therapy.
[Mh] Termos MeSH primário: Anticonvulsivantes/farmacologia
Transdução de Sinais/efeitos dos fármacos
Ácido Valproico/farmacologia
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Neoplasias Encefálicas/metabolismo
Neoplasias Encefálicas/patologia
Proteína Quinase CDC2/metabolismo
Cálcio/metabolismo
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo
Pontos de Checagem do Ciclo Celular
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos da radiação
Raios gama
Glioblastoma/metabolismo
Glioblastoma/patologia
Histona Desacetilases/metabolismo
Seres Humanos
Técnicas de Patch-Clamp
Canais de Potássio/metabolismo
Isoformas de Proteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Potassium Channels); 0 (Protein Isoforms); 614OI1Z5WI (Valproic Acid); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2); EC 2.7.11.22 (CDC2 Protein Kinase); EC 3.5.1.98 (Histone Deacetylases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1159/000485753


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[PMID]:29183753
[Au] Autor:Lee CH; Chu CS; Tsai HJ; Ke LY; Lee HC; Yeh JL; Chen CH; Wu BN
[Ad] Endereço:Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
[Ti] Título:Xanthine-derived KMUP-1 reverses glucotoxicity-activated Kv channels through the cAMP/PKA signaling pathway in rat pancreatic ß cells.
[So] Source:Chem Biol Interact;279:171-176, 2018 Jan 05.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Hyperglycemia-associated glucotoxicity induces ß-cell dysfunction and a reduction in insulin secretion. Voltage-dependent K (Kv) channels in pancreatic ß-cells play a key role in glucose-dependent insulin secretion. KMUP-1, a xanthine derivative, has been demonstrated to modulate Kv channel activity in smooth muscles; however, the role of KMUP-1 in glucotoxicity-activated Kv channels in pancreatic ß-cells remains unclear. In this study we examined the mechanisms by which KMUP-1 could inhibit high glucose (25 mM) activated Kv currents (IKv) in pancreatic ß-cells. Pancreatic ß-cells were isolated from Wistar rats and IKv was monitored by perforated patch-clamp recording. The peak IKv in high glucose-treated ß-cells was ∼1.4-fold greater than for normal glucose (5.6 mM). KMUP-1 (1, 10, 30 µM) prevented high glucose-stimulated IKv in a concentration-dependent manner. Reduction of high glucose-activated IKv was also found for protein kinase A (PKA) activator 8-Br-cAMP (100 µM). Additionally, KMUP-1 (30 µM) current inhibition was reversed by the PKA inhibitor H-89 (1 µM). Otherwise, pretreatment with the PKC activator or inhibitor had no effect on IKv in high glucose exposure. In conclusion, glucotoxicity-diminished insulin secretion was due to IKv activation. KMUP-1 attenuated high glucose-stimulated IKv via the PKA but not the PKC signaling pathway. This finding provides evidence that KMUP-1 might be a promising agent for treating hyperglycemia-induced insulin resistance.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
AMP Cíclico/metabolismo
Glucose/toxicidade
Células Secretoras de Insulina/efeitos dos fármacos
Piperidinas/farmacologia
Canais de Potássio/metabolismo
Xantinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Insulina/secreção
Células Secretoras de Insulina/metabolismo
Ratos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (Piperidines); 0 (Potassium Channels); 0 (Xanthines); 1X0H7WEC5D (KMUP 1); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180103
[Lr] Data última revisão:
180103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE


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[PMID]:29186148
[Au] Autor:Zhu X; Padmanabhan R; Copeland B; Bridgers J; Ren Z; Kamalakaran S; O'Driscoll-Collins A; Berkovic SF; Scheffer IE; Poduri A; Mei D; Guerrini R; Lowenstein DH; Allen AS; Heinzen EL; Goldstein DB
[Ad] Endereço:Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, United States of America.
[Ti] Título:A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations.
[So] Source:PLoS Genet;13(11):e1007104, 2017 Nov.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p<2.68×10-6). In addition, six of the 10 most significantly associated genes are known EE genes, and the majority of the known EE genes (17 out of 25) originally implicated in trio sequencing are nominally significant (p<0.05), a proportion significantly higher than the expected (Fisher's exact p = 2.33×10-17). Our results indicate that a case-control collapsing analysis can identify several of the EE genes originally implicated in trio sequencing studies, and clearly show that additional genes would be implicated with larger sample sizes. The case-control analysis not only makes discovery easier and more economical in early onset disorders, particularly when large cohorts are available, but also supports the use of this approach to identify genes in diseases that present later in life when parents are not readily available.
[Mh] Termos MeSH primário: Epilepsia/genética
Mutação
[Mh] Termos MeSH secundário: Estudos de Casos e Controles
Análise Mutacional de DNA
Feminino
Genes Dominantes
Estudo de Associação Genômica Ampla
Seres Humanos
Masculino
Proteínas Munc18/genética
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Proteínas do Tecido Nervoso/genética
Canais de Potássio/genética
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KCNT1 protein, human); 0 (Munc18 Proteins); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (Nerve Tissue Proteins); 0 (Potassium Channels); 0 (SCN2A protein, human); 0 (STXBP1 protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007104


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[PMID]:29054409
[Au] Autor:Nakashima N; Nakashima K; Nakayama T; Takaku A; Kanamori R
[Ad] Endereço:Division of Integrated Autonomic Function, Department of Physiology, School of Medicine, Kurume University, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan; Department of Physiology and Neurobiology, Faculty of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan. Electronic ad
[Ti] Título:Dual expression of constitutively active Gα -protein-coupled receptors differentially establishes the resting activity of the cAMP-gated HCN2 channel in a single compartment.
[So] Source:Biochem Biophys Res Commun;494(1-2):76-81, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channel is a major subtype of the HCN channel family expressed in the nervous system that sets the membrane potential, regulates cell excitability and senses changes in the extracellular environment. Neurons express various Gα -protein-coupled receptors (GPCRs), many of which show ligand-independent constitutive activity. These membrane-bound proteins are expressed in various subcellular compartments of neurons. Therefore, some proportion of HCN2 channels opens in response to the basal cAMP pool size produced by constitutively active GPCRs. Here, we employed an exogenous HEK293 expression system and voltage-clamp patch-clamp recordings to investigate basal HCN2 channel activity in the presence of two GPCRs with diverse basal activities in a single compartment. We utilized the ß2-adrenoceptor (ß2AR) together with odorant receptors (ORs), as both GPCR families are known to show strong basal activity. Consequently, ß2AR alone strongly enhanced the activity of HCN2 channels, and co-expression of ORs further diversified the HCN2 channel activity, which was totally abolished by an adenylate cyclase inhibitor. Thus, we conclude that the dual expression of constitutively active GPCRs establishes the diverse range of the basal cAMP pool size in resting cells through mutual additive or suppressive interactions, even in the absence of external stimulation.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo
Canais de Potássio/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Células HEK293
Seres Humanos
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética
Ativação do Canal Iônico
Técnicas de Patch-Clamp
Canais de Potássio/genética
Receptores Adrenérgicos beta 2/genética
Receptores Adrenérgicos beta 2/metabolismo
Receptores Acoplados a Proteínas-G/genética
Receptores Odorantes/genética
Receptores Odorantes/metabolismo
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HCN2 protein, human); 0 (Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels); 0 (Potassium Channels); 0 (Receptors, Adrenergic, beta-2); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Odorant); 0 (Recombinant Proteins); E0399OZS9N (Cyclic AMP); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gs)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171022
[St] Status:MEDLINE


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[PMID]:28989025
[Au] Autor:Chan PKW; Geng L; Gao Y; Keung W; Li RA
[Ad] Endereço:Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Stockholm 17177, Sweden.
[Ti] Título:AAV-mediated conversion of human pluripotent stem cell-derived pacemaker.
[So] Source:Biochem Biophys Res Commun;494(1-2):346-351, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Malfunction of nodal pacemaker (Pm) cardiomyocytes (CMs) due to diseases or aging leads to rhythm generation disorders, necessitating electronic Pm implantation. We functionally reprogrammed human pluripotent stem cell (hPSC) derived-ventricular (V) CMs into -PmCMs via recombinant adeno-associated virus serotype 9 (rAAV9)-mediated overexpression of engineered HCN1 channel (HCN1ΔΔΔ) whose S3-S4 linker has been strategically deleted by design to promote cardiac pacemaking. rAAV9-HCN1ΔΔΔ-reprogrammed hPSC-PmCMs converted from -VCMs showed automaticity and action potential parameters typical of native nodal PmCMs. Implantation of rAAV9-HCN1ΔΔΔ-based BPm in a preclinical porcine model of complete heart block significantly reduced the dependence on device-supported pacing and generated spontaneous heart rhythms from the BPm. Collectively, these results have further laid the groundwork on BPm for future translation.
[Mh] Termos MeSH primário: Dependovirus/metabolismo
Bloqueio Cardíaco/terapia
Ventrículos do Coração/metabolismo
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo
Miócitos Cardíacos/metabolismo
Células-Tronco Pluripotentes/metabolismo
Canais de Potássio/metabolismo
[Mh] Termos MeSH secundário: Potenciais de Ação/fisiologia
Animais
Diferenciação Celular
Reprogramação Celular
Dependovirus/genética
Modelos Animais de Doenças
Expressão Gênica
Genes Reporter
Vetores Genéticos/química
Vetores Genéticos/metabolismo
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Bloqueio Cardíaco/genética
Bloqueio Cardíaco/metabolismo
Bloqueio Cardíaco/fisiopatologia
Frequência Cardíaca/fisiologia
Ventrículos do Coração/patologia
Ventrículos do Coração/fisiopatologia
Células-Tronco Embrionárias Humanas/citologia
Células-Tronco Embrionárias Humanas/metabolismo
Seres Humanos
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética
Miócitos Cardíacos/citologia
Marca-Passo Artificial
Células-Tronco Pluripotentes/citologia
Canais de Potássio/genética
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HCN1 protein, human); 0 (Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels); 0 (Potassium Channels); 147336-22-9 (Green Fluorescent Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171010
[St] Status:MEDLINE


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[PMID]:28976980
[Au] Autor:McElroy T; McReynolds CN; Gulledge A; Knight KR; Smith WE; Albrecht EA
[Ad] Endereço:Department of Ecology, Evolution and Organismal Biology, Kennesaw State University, Kennesaw, GA, United States of America.
[Ti] Título:Differential toxicity and venom gland gene expression in Centruroides vittatus.
[So] Source:PLoS One;12(10):e0184695, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Variation in venom toxicity and composition exists in many species. In this study, venom potency and venom gland gene expression was evaluated in Centruroides vittatus, size class I-II (immature) and size class IV (adults/penultimate instars) size classes. Venom toxicity was evaluated by probit analysis and returned ED50 values of 50.1 µg/g for class IV compared to 134.2 µg/g for class I-II 24 hours post injection, suggesting size class IV was 2.7 fold more potent. Next generation sequencing (NGS and qPCR were used to characterize venom gland gene expression. NGS data was assembled into 36,795 contigs, and annotated using BLASTx with UNIPROT. EdgeR analysis of the sequences showed statistically significant differential expression in transcripts associated with sodium and potassium channel modulation. Sodium channel modulator expression generally favored size class IV; in contrast, potassium channel modulators were favored in size class I-II expression. Real-time quantitative PCR of 14 venom toxin transcripts detected relative expression ratios that paralleled NGS data and identified potential family members or splice variants for several sodium channel modulators. Our data suggests ontogenetic differences in venom potency and venom related genes expression exist between size classes I-II and IV.
[Mh] Termos MeSH primário: Venenos de Escorpião/toxicidade
Escorpiões/genética
[Mh] Termos MeSH secundário: Animais
DNA/genética
Sequenciamento de Nucleotídeos em Larga Escala
Canais de Potássio/efeitos dos fármacos
RNA Mensageiro/genética
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Venenos de Escorpião/genética
Escorpiões/anatomia & histologia
Canais de Sódio/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Potassium Channels); 0 (RNA, Messenger); 0 (Scorpion Venoms); 0 (Sodium Channels); 9007-49-2 (DNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184695


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[PMID]:28918294
[Au] Autor:Abd Elmoneim H; Sharabi F; Mohy El Din M; Louedec L; Norel X; Senbel A
[Ad] Endereço:Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
[Ti] Título:Potassium channels modulate the action but not the synthesis of hydrogen sulfide in rat corpus cavernosum.
[So] Source:Life Sci;189:39-43, 2017 Nov 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIM: Hydrogen sulfide (H S) is a newly-introduced gasotransmitter in penile tissues. However, its exact mechanism of action in mediating penile erection is not fully elucidated. The major aim of this study was to examine the role of different K channels in mediating the responses to H S in the corpus cavernosum. MAIN METHODS: Tension studies using isolated rat corpus cavernosum strips were conducted. Endogenous H S production was measured using polarographic technique. Results are expressed as mean±SEM. KEY FINDINGS: l-Cysteine (10 M) stimulated rat corpus cavernosum to produce H S. Blockade of CSE by BCA (10 M) reduced the concentration of H S produced from rat corpus cavernosum significantly. Addition of TEA (10 M) or 4-AP (10 M) didn't have a significant effect on the concentration of H S produced. l-Cysteine (10 -10 M) elicited a concentration-dependent relaxation response which was significantly reduced by blockade of CSE using BCA (10 M). TEA (10 M), 4-AP (10 M) and TEA (10 M) attenuated l-cysteine-induced relaxation significantly. At 10 M, l-cysteine resulted in percentage relaxation of 1.55±0.63, 10.94±1.93 and 1.93±0.80 in presence of TEA (10 M), 4-AP (10 M) and TEA (10 M) respectively compared to 23.78±2.71 as control. Both glibenclamide (10 M) and BaCl (3×10 M) failed to reduce these relaxations significantly. SIGNIFICANCE: H S-induced relaxation of rat corpus cavernosum may be mediated - at least in part - through BK and K channels not by K and K channels. It also seems that K -channels do not contribute to the synthesis of H S.
[Mh] Termos MeSH primário: Sulfeto de Hidrogênio/metabolismo
Pênis/metabolismo
Canais de Potássio/metabolismo
[Mh] Termos MeSH secundário: Alanina/administração & dosagem
Alanina/análogos & derivados
Alanina/farmacologia
Animais
Cisteína/administração & dosagem
Cisteína/farmacologia
Relação Dose-Resposta a Droga
Glibureto/farmacologia
Masculino
Ratos
Ratos Wistar
Tetraetilamônio/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Potassium Channels); 66-40-0 (Tetraethylammonium); 923-01-3 (3-cyanoalanine); K848JZ4886 (Cysteine); OF5P57N2ZX (Alanine); SX6K58TVWC (Glyburide); YY9FVM7NSN (Hydrogen Sulfide)
[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:170918
[St] Status:MEDLINE


  8 / 25044 MEDLINE  
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[PMID]:28864772
[Au] Autor:Bankston JR; DeBerg HA; Stoll S; Zagotta WN
[Ad] Endereço:From the Departments of Physiology and Biophysics and.
[Ti] Título:Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b.
[So] Source:J Biol Chem;292(43):17794-17803, 2017 Oct 27.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:TRIP8b, an accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, alters both the cell surface expression and cyclic nucleotide dependence of these channels. However, the mechanism by which TRIP8b exerts these dual effects is still poorly understood. In addition to binding to the carboxyl-terminal tripeptide of HCN channels, TRIP8b also binds directly to the cyclic nucleotide-binding domain (CNBD). That interaction, which requires a small central portion of TRIP8b termed TRIP8b , is both necessary and sufficient for reducing the cAMP-dependent regulation of HCN channels. Here, using fluorescence anisotropy, we report that TRIP8b binding to the CNBD of HCN2 channels decreases the apparent affinity of cAMP for the CNBD. We explored two possible mechanisms for this inhibition. A noncompetitive mechanism in which TRIP8b inhibits the conformational change of the CNBD associated with cAMP regulation and a competitive mechanism in which TRIP8b and cAMP compete for the same binding site. To test these two mechanisms, we used a combination of fluorescence anisotropy, biolayer interferometry, and double electron-electron resonance spectroscopy. Fitting these models to our fluorescence anisotropy binding data revealed that, surprisingly, the TRIP8b-dependent reduction of cAMP binding to the CNBD can largely be explained by partial competition between TRIP8b and cAMP. On the basis of these findings, we propose that TRIP8b competes with a portion of the cAMP-binding site or distorts the binding site by making interactions with the binding pocket, thus acting predominantly as a competitive antagonist that inhibits the cyclic-nucleotide dependence of HCN channels.
[Mh] Termos MeSH primário: AMP Cíclico
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização
Canais de Potássio
Receptores Citoplasmáticos e Nucleares
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
AMP Cíclico/química
AMP Cíclico/genética
AMP Cíclico/metabolismo
Seres Humanos
Domínios Proteicos
Receptores Citoplasmáticos e Nucleares/química
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HCN2 protein, human); 0 (Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels); 0 (Pex5R protein, human); 0 (Potassium Channels); 0 (Receptors, Cytoplasmic and Nuclear); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171104
[Lr] Data última revisão:
171104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.800722


  9 / 25044 MEDLINE  
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[PMID]:28864420
[Au] Autor:Ellekvist P; Mlambo G; Kumar N; Klaerke DA
[Ad] Endereço:Medical Department, Herlev & Gentofte Hospital, Copenhagen, Denmark. Electronic address: p.ellekvist@dadlnet.dk.
[Ti] Título:Functional characterization of malaria parasites deficient in the K channel Kch2.
[So] Source:Biochem Biophys Res Commun;493(1):690-696, 2017 Nov 04.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:K channels are integral membrane proteins, which contribute to maintain vital parameters such as the cellular membrane potential and cell volume. Malaria parasites encode two K channel homologues, Kch1 and Kch2, which are well-conserved among members of the Plasmodium genus. In the rodent malaria parasite P. berghei, the functional significance of K channel homologue PbKch2 was studied using targeted gene knock-out. The knockout parasites were characterized in a mouse model in terms of growth-kinetics and infectivity in the mosquito vector. Furthermore, using a tracer-uptake technique with Rb as a K congener, the K transporting properties of the knockout parasites were assessed. RESULTS: Genetic disruption of Kch2 did not grossly affect the phenotype in terms of asexual replication and pathogenicity in a mouse model. In contrast to Kch1-null parasites, Kch2-null parasites were fully capable of forming oocysts in female Anopheles stephensi mosquitoes. Rb uptake in Kch2-deficient blood-stage P. berghei parasites (Kch2-null) did not differ from that of wild-type (WT) parasites. About two-thirds of the Rb uptake in WT and in Kch2-null parasites could be inhibited by K channel blockers and could be inferred to the presence of functional Kch1 in Kch2 knockout parasites. Kch2 is therefore not required for transport of K in P. berghei and is not essential to mosquito-stage sporogonic development of the parasite.
[Mh] Termos MeSH primário: Anopheles/parasitologia
Malária/parasitologia
Plasmodium berghei/metabolismo
Plasmodium berghei/patogenicidade
Canais de Potássio/metabolismo
Proteínas de Protozoários/metabolismo
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
Camundongos
Plasmodium berghei/genética
Canais de Potássio/genética
Proteínas de Protozoários/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Potassium Channels); 0 (Protozoan Proteins)
[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:170903
[St] Status:MEDLINE


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[PMID]:28832658
[Au] Autor:Deng XL; Wang Y; Xiao GS
[Ad] Endereço:Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
[Ti] Título:Effects of equol on multiple K+ channels stably expressed in HEK 293 cells.
[So] Source:PLoS One;12(8):e0183708, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The present study investigated the effects of equol on cardiovascular K+ channel currents. The cardiovascular K+ channel currents were determined in HEK 293 cells stably expressing cloned differential cardiovascular K+ channels with conventional whole-cell patch voltage-clamp technique. We found that equol inhibited hKv1.5 (IC50: 15.3 µM), hKv4.3 (IC50: 29.2 µM and 11.9 µM for hKv4.3 peak current and charge area, respectively), IKs (IC50: 24.7 µM) and IhERG (IC50: 31.6 and 56.5 µM for IhERG.tail and IhERG.step, respectively), but not hKir2.1 current, in a concentration-dependent manner. Interestingly, equol increased BKCa current with an EC50 of 0.1 µM. It had no significant effect on guinea pig ventricular action potentials at concentrations of ≤3 µM. These results demonstrate that equol inhibits several cardiac K+ currents at relatively high concentrations, whereas it increases BKCa current at very low concentrations, suggesting that equol is a safe drug candidate for treating patients with cerebral vascular disorders.
[Mh] Termos MeSH primário: Equol/farmacologia
Canais de Potássio/efeitos dos fármacos
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Animais
Cobaias
Células HEK293
Ventrículos do Coração/efeitos dos fármacos
Seres Humanos
Canais de Potássio/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Potassium Channels); 531-95-3 (Equol)
[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:170824
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183708



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