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Pesquisa : D12.776.157.530.400.175.781 [Categoria DeCS]
Referências encontradas : 2335 [refinar]
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  1 / 2335 MEDLINE  
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[PMID]:28470528
[Au] Autor:Kuenzel K; Mofrad SA; Gilbert DF
[Ad] Endereço:Institute of Medical Biotechnology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052, Erlangen, Germany. Katharina.kuenzel@fau.de.
[Ti] Título:Phenotyping Cellular Viability by Functional Analysis of Ion Channels: GlyR-Targeted Screening in NT2-N Cells.
[So] Source:Methods Mol Biol;1601:205-214, 2017.
[Is] ISSN:1940-6029
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glycine receptor chloride channels (GlyRs) are attractive drug targets for therapeutic intervention and are also more and more recognized in the context of in vitro neurotoxicity and developmental neurotoxicity testing. Assaying the functional properties of GlyR can serve as an indicator of cellular viability and the integrity of the developing and mature central nervous system. Human pluripotent NTERA-2 (NT2) stem cells undergo neuronal differentiation upon stimulation with retinoic acid and express a large variety of neuronal proteins-including GlyR. YFP-I152L, a halide-sensitive variant of yellow fluorescent protein, allows high-throughput fluorescence-based functional analysis of GlyRs in NT2 cells. Here we describe a protocol for phenotyping of cellular viability by functional analysis of GlyR in neuronally differentiated NT2 (NT2-N) cells using YFP-I152L as a reporter of functional integrity of GlyRs. The protocol describes neuronal differentiation of NT2 stem cells, transient transfection of NT2-N cells with YFP-I152L as well as functional imaging and analysis of data from high-content imaging.
[Mh] Termos MeSH primário: Sobrevivência Celular
Células-Tronco de Carcinoma Embrionário/citologia
Neurogênese
Neurônios/citologia
Células-Tronco Pluripotentes/citologia
Receptores da Glicina/metabolismo
[Mh] Termos MeSH secundário: Diferenciação Celular
Avaliação Pré-Clínica de Medicamentos
Células-Tronco de Carcinoma Embrionário/efeitos dos fármacos
Seres Humanos
Proteínas Luminescentes/metabolismo
Neurogênese/efeitos dos fármacos
Imagem Óptica/métodos
Tretinoína/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Luminescent Proteins); 0 (Receptors, Glycine); 5688UTC01R (Tretinoin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1007/978-1-4939-6960-9_16


  2 / 2335 MEDLINE  
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[PMID]:28985719
[Au] Autor:Yang Z; Sun G; Yao F; Tao D; Zhu B
[Ad] Endereço:Department of Pediatrics, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. sizhewujiu@163.com.
[Ti] Título:A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature.
[So] Source:BMC Med Genet;18(1):110, 2017 Oct 06.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The pathogenesis of hereditary hyperekplexia is thought to involve abnormalities in the glycinergic neurotransmission system, the most of mutations reported in GLRA1. This gene encodes the glycine receptor α1 subunit, which has an extracellular domain (ECD) and a transmembrane domain (TMD) with 4 α-helices (TM1-TM4). CASE PRESENTATION: We investigated the genetic cause of hyperekplexia in a Chinese family with one affected member. Whole-exome sequencing of the 5 candidate genes was performed on the proband patient, and direct sequencing was performed to validate and confirm the detected mutation in other family members. We also review and analyse all reported GLRA1 mutations. The proband had a compound heterozygous GLRA1 mutation that comprised 2 novel GLRA1 missense mutations, C.569C > T (p.T190 M) from the mother and C.1270G > A (p.D424N) from the father. SIFT, Polyphen-2 and MutationTaster analysis identified the mutations as disease-causing, but the parents had no signs of hyperekplexia. The p.T190 M mutation is located in the ECD, while p.D424N is located in TM4. CONCLUSIONS: Our findings contribute to a growing list GLRA1 mutations associated with hyperekplexia and provide new insights into correlations between phenotype and GLRA1 mutations. Some recessive mutations can induce hyperekplexia in combination with other recessive GLRA1 mutations. Mutations in the ECD, TM1, TM1-TM2 loop, TM3, TM3-TM4 loop and TM4 are more often recessive and part of a compound mutation, while those in TM2 and the TM2-TM3 loop are more likely to be dominant hereditary mutations.
[Mh] Termos MeSH primário: Hiperecplexia/genética
Mutação
Receptores da Glicina/genética
[Mh] Termos MeSH secundário: Adolescente
China
Feminino
Loci Gênicos/genética
Seres Humanos
Hiperecplexia/diagnóstico
Hiperecplexia/fisiopatologia
Lactente
Masculino
Linhagem
Fenótipo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Glycine); 0 (glycine receptor alpha1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171008
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0476-6


  3 / 2335 MEDLINE  
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[PMID]:28751111
[Au] Autor:Poudel S; Kim Y; Gwak JS; Jeong S; Lee Y
[Ad] Endereço:Department of Bio and Fermentation Convergence Technology, BK21 PLUS Project, Kookmin University, Seoul 02707, South Korea.
[Ti] Título:Gustatory receptor 22e is essential for sensing chloroquine and strychnine in Drosophila melanogaster.
[So] Source:Insect Biochem Mol Biol;88:30-36, 2017 Sep.
[Is] ISSN:1879-0240
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chloroquine, an amino quinolone derivative commonly used as an anti-malarial drug, is known to impart an unpleasant taste. Little research has been done to study chloroquine taste in insects, therefore, we examined both the deterrant properties and mechanisms underlying chloroquine perception in fruit flies. We identified the antifeedant effect of chloroquine by screening 21 gustatory receptor (Grs) mutants through behavioral feeding assays and electrophysiology experiments. We discovered that two molecular sensors, GR22e and GR33a, act as chloroquine receptors, and found that chloroquine-mediated activation of GRNs occurs through S-type sensilla. At the same time, we successfully recapitulated the chloroquine receptor by expressing GR22e in ectopic gustatory receptor neurons. We also found that GR22e forms a part of the strychnine receptor. We suggest that the Drosophila strychnine receptor might have a very complex structure since five different GRs are required for strychnine-induced action potentials.
[Mh] Termos MeSH primário: Proteínas de Drosophila/metabolismo
Drosophila melanogaster/metabolismo
Receptores de Superfície Celular/metabolismo
Receptores de Droga/isolamento & purificação
Receptores da Glicina/isolamento & purificação
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Animais
Cloroquina/metabolismo
Drosophila melanogaster/química
Drosophila melanogaster/efeitos dos fármacos
Feminino
Masculino
Neurônios Receptores Olfatórios/efeitos dos fármacos
Neurônios Receptores Olfatórios/metabolismo
Receptores de Droga/metabolismo
Receptores da Glicina/metabolismo
Sensilas/metabolismo
Estricnina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Receptors, Cell Surface); 0 (Receptors, Drug); 0 (Receptors, Glycine); 0 (chloroquine receptor); 0 (gustatory receptor, Drosophila); 0 (strychnine receptor); 886U3H6UFF (Chloroquine); H9Y79VD43J (Strychnine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE


  4 / 2335 MEDLINE  
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[PMID]:28724750
[Au] Autor:Schaefer N; Berger A; van Brederode J; Zheng F; Zhang Y; Leacock S; Littau L; Jablonka S; Malhotra S; Topf M; Winter F; Davydova D; Lynch JW; Paige CJ; Alzheimer C; Harvey RJ; Villmann C
[Ad] Endereço:Institute of Clinical Neurobiology, Julius-Maximilians-University of Würzburg, 97078 Würzburg, Germany.
[Ti] Título:Disruption of a Structurally Important Extracellular Element in the Glycine Receptor Leads to Decreased Synaptic Integration and Signaling Resulting in Severe Startle Disease.
[So] Source:J Neurosci;37(33):7948-7961, 2017 Aug 16.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Functional impairments or trafficking defects of inhibitory glycine receptors (GlyRs) have been linked to human hyperekplexia/startle disease and autism spectrum disorders. We found that a lack of synaptic integration of GlyRs, together with disrupted receptor function, is responsible for a lethal startle phenotype in a novel spontaneous mouse mutant , caused by a missense mutation, Q177K, located in the extracellular ß8-ß9 loop of the GlyR α1 subunit. Recently, structural data provided evidence that the flexibility of the ß8-ß9 loop is crucial for conformational transitions during opening and closing of the ion channel and represents a novel allosteric binding site in Cys-loop receptors. We identified the underlying neuropathological mechanisms in male and female mice through a combination of protein biochemistry, immunocytochemistry, and both and in electrophysiology. Increased expression of the mutant GlyR α1 subunit was not sufficient to compensate for a decrease in synaptic integration of α1 ß GlyRs. The remaining synaptic heteromeric α1 ß GlyRs had decreased current amplitudes with significantly faster decay times. This functional disruption reveals an important role for the GlyR α1 subunit ß8-ß9 loop in initiating rearrangements within the extracellular-transmembrane GlyR interface and that this structural element is vital for inhibitory GlyR function, signaling, and synaptic clustering. GlyR dysfunction underlies neuromotor deficits in startle disease and autism spectrum disorders. We describe an extracellular GlyR α1 subunit mutation (Q177K) in a novel mouse startle disease mutant Structural data suggest that during signal transduction, large transitions of the ß8-ß9 loop occur in response to neurotransmitter binding. Disruption of the ß8-ß9 loop by the Q177K mutation results in a disruption of hydrogen bonds between Q177 and the ligand-binding residue R65. Functionally, the Q177K change resulted in decreased current amplitudes, altered desensitization decay time constants, and reduced GlyR clustering and synaptic strength. The GlyR ß8-ß9 loop is therefore an essential regulator of conformational rearrangements during ion channel opening and closing.
[Mh] Termos MeSH primário: Receptores da Glicina/genética
Receptores da Glicina/metabolismo
Rigidez Muscular Espasmódica/genética
Rigidez Muscular Espasmódica/metabolismo
Sinapses/genética
Sinapses/metabolismo
[Mh] Termos MeSH secundário: Animais
Líquido Extracelular/metabolismo
Feminino
Células HEK293
Seres Humanos
Ativação do Canal Iônico/fisiologia
Masculino
Camundongos
Camundongos da Linhagem 129
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Neurônios Motores/metabolismo
Mutação de Sentido Incorreto/fisiologia
Estrutura Secundária de Proteína
Receptores da Glicina/química
Índice de Gravidade de Doença
Medula Espinal/metabolismo
Transmissão Sináptica/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Glycine); 0 (glycine receptor alpha1)
[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:170721
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0009-17.2017


  5 / 2335 MEDLINE  
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[PMID]:28716844
[Au] Autor:Cantaut-Belarif Y; Antri M; Pizzarelli R; Colasse S; Vaccari I; Soares S; Renner M; Dallel R; Triller A; Bessis A
[Ad] Endereço:École Normale Supérieure, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Paris Sciences et Lettres Research University, Paris, France.
[Ti] Título:Microglia control the glycinergic but not the GABAergic synapses via prostaglandin E2 in the spinal cord.
[So] Source:J Cell Biol;216(9):2979-2989, 2017 Sep 04.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Microglia control excitatory synapses, but their role in inhibitory neurotransmission has been less well characterized. Herein, we show that microglia control the strength of glycinergic but not GABAergic synapses via modulation of the diffusion dynamics and synaptic trapping of glycine (GlyR) but not GABA receptors. We further demonstrate that microglia regulate the activity-dependent plasticity of glycinergic synapses by tuning the GlyR diffusion trap. This microglia-synapse cross talk requires production of prostaglandin E2 by microglia, leading to the activation of neuronal EP2 receptors and cyclic adenosine monophosphate-dependent protein kinase. Thus, we now provide a link between microglial activation and synaptic dysfunctions, which are common early features of many brain diseases.
[Mh] Termos MeSH primário: Dinoprostona/metabolismo
Sinapses Elétricas/metabolismo
Glicina/metabolismo
Microglia/metabolismo
Inibição Neural
Medula Espinal/metabolismo
Transmissão Sináptica
Ácido gama-Aminobutírico/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Células Cultivadas
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Difusão
Feminino
Masculino
Potenciais da Membrana
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Transporte Proteico
Receptores de GABA-A/metabolismo
Receptores da Glicina/metabolismo
Receptores de Prostaglandina E Subtipo EP2/metabolismo
Membranas Sinápticas/metabolismo
Fatores de Tempo
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Membrane Proteins); 0 (Ptger2 protein, mouse); 0 (Receptors, GABA-A); 0 (Receptors, Glycine); 0 (Receptors, Prostaglandin E, EP2 Subtype); 0 (gephyrin); 56-12-2 (gamma-Aminobutyric Acid); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); K7Q1JQR04M (Dinoprostone); TE7660XO1C (Glycine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201607048


  6 / 2335 MEDLINE  
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[PMID]:28575722
[Au] Autor:Chakka N; Andrews KL; Berry LM; Bregman H; Gunaydin H; Huang L; Guzman-Perez A; Plant MH; Simard JR; Gingras J; DiMauro EF
[Ad] Endereço:Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
[Ti] Título:Applications of parallel synthetic lead hopping and pharmacophore-based virtual screening in the discovery of efficient glycine receptor potentiators.
[So] Source:Eur J Med Chem;137:63-75, 2017 Sep 08.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Glycine receptors (GlyRs) are pentameric glycine-gated chloride ion channels that are enriched in the brainstem and spinal cord where they have been demonstrated to play a role in central nervous system (CNS) inhibition. Herein we describe two novel classes of glycine receptor potentiators that have been developed using similarity- and property-guided scaffold hopping enabled by parallel synthesis and pharmacophore-based virtual screening strategies. This effort resulted in the identification of novel, efficient and modular leads having favorable in vitro ADME profiles and high CNS multi-parameter optimization (MPO) scores, exemplified by azetidine sulfonamide 19 and aminothiazole sulfone (ent2)-20.
[Mh] Termos MeSH primário: Descoberta de Drogas
Receptores da Glicina/antagonistas & inibidores
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Avaliação Pré-Clínica de Medicamentos
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Glycine); 0 (Sulfonamides)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE


  7 / 2335 MEDLINE  
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[PMID]:28501123
[Au] Autor:Brencher L; Verhaegh R; Kirsch M
[Ad] Endereço:Institut für Physiologische Chemie, Universitätsklinikum Essen, Universität Duisburg-Essen, Germany.
[Ti] Título:Attenuation of intestinal ischemia-reperfusion-injury by ß-alanine: a potentially glycine-receptor mediated effect.
[So] Source:J Surg Res;211:233-241, 2017 May 01.
[Is] ISSN:1095-8673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Acute mesenteric ischemia is often caused by embolization of the mesenteric arterial circulation. Coherent intestinal injury due to ischemia and following reperfusion get visible on macroscopic and histologic level. In previous studies, application of glycine caused an ameliorated intestinal damage after ischemia-reperfusion in rats. Because we speculated that glycine acted here as a signal molecule, we investigated whether the glycine-receptor agonist ß-alanine evokes the same beneficial effect in intestinal ischemia-reperfusion. MATERIALS AND METHODS: ß-alanine (10, 30, and 100 mg/kg) was administered intravenously. Ischemia/reperfusion of the small intestine was initiated by occluding and reopening the superior mesenteric artery in rats. After 90 min of ischemia and 120 min of reperfusion, the intestine was analyzed with regard to macroscopic and histologic tissue damage, the activity of the saccharase, and accumulation of macrophages. In addition, systemic parameters and metabolic ones (e.g., acid-base balance, electrolytes, and blood glucose) were measured at certain points in time. RESULTS: All three dosages of ß-alanine did not change systemic parameters but prevent from hyponatremia during the period of reperfusion. Most importantly, application of 100-mg ß-alanine clearly diminished intestinal tissue damage, getting visible on macroscopic and histologic level. In addition, I/R-mediated decrease of saccharase activity and accumulation of macrophages in the small intestine were ameliorated. CONCLUSIONS: The present study demonstrated that ß-alanine was a potent agent to ameliorate I/R-induced injury of the small intestine. Due to its diminishing effect on the accumulation of macrophages, ß-alanine is strongly expected to mediate its beneficial effect via glycine receptors.
[Mh] Termos MeSH primário: Intestinos/irrigação sanguínea
Substâncias Protetoras/uso terapêutico
Traumatismo por Reperfusão/prevenção & controle
beta-Alanina/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Biomarcadores/metabolismo
Relação Dose-Resposta a Droga
Injeções Intravenosas
Intestinos/efeitos dos fármacos
Intestinos/patologia
Masculino
Substâncias Protetoras/metabolismo
Substâncias Protetoras/farmacologia
Ratos
Ratos Wistar
Receptores da Glicina/metabolismo
beta-Alanina/metabolismo
beta-Alanina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Protective Agents); 0 (Receptors, Glycine); 11P2JDE17B (beta-Alanine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170515
[St] Status:MEDLINE


  8 / 2335 MEDLINE  
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[PMID]:28437460
[Au] Autor:Ranft J; Almeida LG; Rodriguez PC; Triller A; Hakim V
[Ad] Endereço:Laboratoire Physique Statistique, CNRS, Ecole Normale Supérieure, PSL Research University, Université Pierre et Marie Curie, Paris, France.
[Ti] Título:An aggregation-removal model for the formation and size determination of post-synaptic scaffold domains.
[So] Source:PLoS Comput Biol;13(4):e1005516, 2017 Apr.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The formation and stability of synapses are key questions in neuroscience. Post-synaptic domains have been classically conceived as resulting from local insertion and turnover of proteins at the synapse. However, insertion is likely to occur outside the post-synaptic domains and advances in single-molecule imaging have shown that proteins diffuse in the plane of the membrane prior to their accumulation at synapses. We quantitatively investigated this scenario using computer simulations and mathematical analysis, taking for definiteness the specific case of inhibitory synapse components, i.e., the glycine receptor (GlyR) and the associated gephyrin scaffolding protein. The observed domain sizes of scaffold clusters can be explained by a dynamic balance between the aggregation of gephyrin proteins diffusing while bound to GlyR and their turnover at the neuron membrane. We also predict the existence of extrasynaptic clusters with a characteristic size distribution that significantly contribute to the size fluctuations of synaptic domains. New super-resolution data for gephyrin proteins established the existence of extrasynaptic clusters the sizes of which are consistent with the model predictions in a range of model parameters. At a general level, our results highlight aggregation with removal as a non-equilibrium phase separation which produces structures of tunable size.
[Mh] Termos MeSH primário: Modelos Neurológicos
Neurônios/metabolismo
Sinapses/química
Sinapses/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/química
Proteínas de Transporte/metabolismo
Células Cultivadas
Simulação por Computador
Proteínas de Membrana/química
Proteínas de Membrana/metabolismo
Tamanho da Partícula
Ratos Sprague-Dawley
Receptores da Glicina/química
Receptores da Glicina/metabolismo
Medula Espinal/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Membrane Proteins); 0 (Receptors, Glycine); 0 (gephyrin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170425
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005516


  9 / 2335 MEDLINE  
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[PMID]:28429370
[Au] Autor:Langlhofer G; Villmann C
[Ad] Endereço:Institute for Clinical Neurobiology, Julius-Maximilians-University of Würzburg, Würzburg, Germany.
[Ti] Título:The role of charged residues in independent glycine receptor folding domains for intermolecular interactions and ion channel function.
[So] Source:J Neurochem;142(1):41-55, 2017 Jul.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Glycine receptor (GlyR) truncations in the intracellular TM3-4 loop, documented in patients suffering from hyperekplexia and in the mouse mutant oscillator, lead to non-functionality of GlyRs. The missing part that contains the TM3-4 loop, TM4 and C-terminal sequences is essential for pentameric receptor arrangements. In vitro co-expressions of GlyRα1-truncated N-domains and C-domains were able to restore ion channel function. An ionic interaction between both domains was hypothesized as the underlying mechanism. Here, we analysed the proposed ionic interaction between GlyR N- and C-domains using C-terminal constructs with either positively or negatively charged N-termini. Charged residues at the N-terminus of the C-domain did interfere with receptor surface expression and ion channel function. In particular, presence of negatively charged residues at the N-terminus led to significantly decreased ion channel function. Presence of positive charges resulted in reduced maximal currents possibly as a result of repulsion of both domains. If the C-domain was tagged by a myc-epitope, low maximal current amplitudes were detected. Intrinsic charges of the myc-epitope and charged N-terminal ends of the C-domain most probably induce intramolecular interactions. These interactions might hinder the close proximity of C-domains and N-domains, which is a prerequisite for functional ion channel configurations. The remaining basic subdomains close to TM3 and 4 were sufficient for domain complementation and functional ion channel formation. Thus, these basic subdomains forming α-helical elements or an intracellular portal represent attractants for incoming negatively charged chloride ions and interact with the phospholipids thereby stabilizing the GlyR in a conformation that allows ion channel opening.
[Mh] Termos MeSH primário: Canais Iônicos/metabolismo
Receptores da Glicina/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Biotinilação/genética
Fenômenos Eletrofisiológicos/genética
Células HEK293
Seres Humanos
Ativação do Canal Iônico
Canais Iônicos/genética
Conformação Molecular
Mutagênese Sítio-Dirigida
Dobramento de Proteína
Estrutura Terciária de Proteína
Receptores da Glicina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ion Channels); 0 (Receptors, Glycine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14049


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[PMID]:28254751
[Au] Autor:Conceição EP; Madden CJ; Morrison SF
[Ad] Endereço:Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon santosda@ohsu.edu.
[Ti] Título:Glycinergic inhibition of BAT sympathetic premotor neurons in rostral raphe pallidus.
[So] Source:Am J Physiol Regul Integr Comp Physiol;312(6):R919-R926, 2017 06 01.
[Is] ISSN:1522-1490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The rostral raphe pallidus (rRPa) contains sympathetic premotor neurons controlling thermogenesis in brown adipose tissue (BAT). We sought to determine whether a tonic activation of glycine receptors (Gly R) in the rRPa contributes to the inhibitory regulation of BAT sympathetic nerve activity (SNA) and of cardiovascular parameters in anesthetized rats. Nanoinjection of the Gly R antagonist, strychnine (STR), into the rRPa of intact rats increased BAT SNA (peak: +495%), BAT temperature (T , +1.1°C), expired CO , (+0.4%), core body temperature (T , +0.2°C), mean arterial pressure (MAP, +4 mmHg), and heart rate (HR, +57 beats/min). STR into rRPa in rats with a postdorsomedial hypothalamus transection produced similar increases in BAT thermogenic and cardiovascular parameters. Glycine nanoinjection into the rRPa evoked a potent inhibition of the cooling-evoked increases in BAT SNA (nadir: -74%), T (-0.2°C), T (-0.2°C), expired CO (-0.2%), MAP (-8 mmHg), and HR (-22 beats/min) but had no effect on the increases in these variables evoked by STR nanoinjection into rRPa. Nanoinjection of GABA into the rRPa inhibited the STR-evoked BAT SNA (nadir: -86%) and reduced the expired CO (-0.4%). Blockade of glutamate receptors in rRPa reduced the STR-evoked increases in BAT SNA (nadir: -61%), T (-0.5°C), expired CO (-0.3%), MAP (-9 mmHg), and HR (-33 beats/min). We conclude that a tonically active glycinergic input to the rRPa contributes to the inhibitory regulation of the discharge of BAT sympathetic premotor neurons and of BAT thermogenesis and energy expenditure.
[Mh] Termos MeSH primário: Tecido Adiposo Marrom/inervação
Sistema Cardiovascular/inervação
Glicina/metabolismo
Núcleos da Rafe do Mesencéfalo/metabolismo
Neurônios Motores/metabolismo
Inibição Neural
Receptores da Glicina/metabolismo
Sistema Nervoso Simpático/metabolismo
Termogênese
[Mh] Termos MeSH secundário: Potenciais de Ação
Animais
Pressão Arterial
Glicinérgicos/administração & dosagem
Frequência Cardíaca
Injeções
Masculino
Núcleos da Rafe do Mesencéfalo/efeitos dos fármacos
Neurônios Motores/efeitos dos fármacos
Inibição Neural/efeitos dos fármacos
Ratos Sprague-Dawley
Receptores da Glicina/antagonistas & inibidores
Sistema Nervoso Simpático/efeitos dos fármacos
Termogênese/efeitos dos fármacos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycine Agents); 0 (Receptors, Glycine); TE7660XO1C (Glycine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE
[do] DOI:10.1152/ajpregu.00551.2016



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