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[PMID]:28453728
[Au] Autor:Vincent A; Sportouch C; Covinhes A; Barrère C; Gallot L; Delgado-Betancourt V; Lattuca B; Solecki K; Boisguérin P; Piot C; Nargeot J; Barrère-Lemaire S
[Ad] Endereço:IGF, CNRS, INSERM, Univ. Montpellier, F-34094 Montpellier, France.
[Ti] Título:Cardiac mGluR1 metabotropic receptors in cardioprotection.
[So] Source:Cardiovasc Res;113(6):644-655, 2017 May 01.
[Is] ISSN:1755-3245
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aims: In a previous study using a genome-wide microarray strategy, we identified metabotropic glutamate receptor 1 (mGluR1) as a putative cardioprotective candidate in ischaemic postconditioning (PostC). In the present study, we investigated the role of cardiac mGluR1 receptors during cardioprotection against myocardial ischaemia-reperfusion injury in the mouse myocardium. Methods and results: mGluR1 activation by glutamate administered 5 min before reperfusion in C57Bl/6 mice subjected to a myocardial ischaemia protocol strongly decreased both infarct size and DNA fragmentation measured at 24 h reperfusion. This cardioprotective effect was mimicked by the mGluR1 agonist, DHPG (10 µM), and abolished when glutamate was coinjected with the mGluR1 antagonist YM298198 (100 nM). Wortmannin (100 nM), an inhibitor of PI3-kinase, was able to prevent glutamate-induced cardioprotection. A glutamate bolus at the onset of reperfusion failed to protect the heart of mGluR1 knockout mice subjected to a myocardial ischaemia-reperfusion protocol, although PostC still protected the mGluR1 KO mice. Glutamate-treatment improved post-infarction functional recovery as evidenced by an echocardiographic study performed 15 days after treatment and by a histological evaluation of fibrosis 21 days post-treatment. Interestingly, restoration of functional mGluR1s by a PostC stimulus was evidenced at the transcriptional level. Since mGluR1s were localized at the surface membrane of cardiomyocytes, they might contribute to the cardioprotective effect of ischaemic PostC as other Gq-coupled receptors. Conclusion: This study provides the first demonstration that mGluR1 activation at the onset of reperfusion induces cardioprotection and might represent a putative strategy to prevent ischaemia-reperfusion injury.
[Mh] Termos MeSH primário: Agonistas de Aminoácidos Excitatórios/administração & dosagem
Glutamina/administração & dosagem
Infarto do Miocárdio/prevenção & controle
Traumatismo por Reperfusão Miocárdica/prevenção & controle
Miocárdio/metabolismo
Receptores de Glutamato Metabotrópico/agonistas
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Antagonistas de Aminoácidos Excitatórios/farmacologia
Predisposição Genética para Doença
Camundongos Endogâmicos C57BL
Camundongos Knockout
Infarto do Miocárdio/metabolismo
Infarto do Miocárdio/patologia
Infarto do Miocárdio/fisiopatologia
Traumatismo por Reperfusão Miocárdica/metabolismo
Traumatismo por Reperfusão Miocárdica/patologia
Traumatismo por Reperfusão Miocárdica/fisiopatologia
Miocárdio/patologia
Fenótipo
Fosfatidilinositol 3-Quinase/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptores de Glutamato Metabotrópico/deficiência
Receptores de Glutamato Metabotrópico/genética
Transdução de Sinais
Fatores de Tempo
Função Ventricular Esquerda/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Excitatory Amino Acid Agonists); 0 (Excitatory Amino Acid Antagonists); 0 (Receptors, Metabotropic Glutamate); 0 (metabotropic glutamate receptor type 1); 0RH81L854J (Glutamine); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/cvr/cvx024


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[PMID]:29339723
[Au] Autor:Elia J; Ungal G; Kao C; Ambrosini A; De Jesus-Rosario N; Larsen L; Chiavacci R; Wang T; Kurian C; Titchen K; Sykes B; Hwang S; Kumar B; Potts J; Davis J; Malatack J; Slattery E; Moorthy G; Zuppa A; Weller A; Byrne E; Li YR; Kraft WK; Hakonarson H
[Ad] Endereço:Nemours, du Pont Hospital for Children, Wilmington, 19803, DE, USA. Josephine.Elia@nemours.org.
[Ti] Título:Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling.
[So] Source:Nat Commun;9(1):4, 2018 01 16.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12-17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50-800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 at baseline vs. 2.33 at week 5 (P < 0.001) and 4.83 at baseline vs. 3.86 at week 5 (P < 0.001). Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants (P < 0.035). There were no differences in the incidence of adverse events between placebo week and weeks on active drug. The trial is registered at https://clinicaltrials.gov/ct2/show/study/NCT02286817 .
[Mh] Termos MeSH primário: Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico
Fármacos atuantes sobre Aminoácidos Excitatórios/uso terapêutico
Receptores de Glutamato Metabotrópico/genética
[Mh] Termos MeSH secundário: Adolescente
Área Sob a Curva
Transtorno do Deficit de Atenção com Hiperatividade/genética
Criança
Relação Dose-Resposta a Droga
Método Duplo-Cego
Fármacos atuantes sobre Aminoácidos Excitatórios/administração & dosagem
Fármacos atuantes sobre Aminoácidos Excitatórios/efeitos adversos
Fármacos atuantes sobre Aminoácidos Excitatórios/farmacocinética
Feminino
Meia-Vida
Seres Humanos
Masculino
Mutação
Receptores de Glutamato Metabotrópico/efeitos dos fármacos
Método Simples-Cego
[Pt] Tipo de publicação:CONTROLLED CLINICAL TRIAL; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Excitatory Amino Acid Agents); 0 (Receptors, Metabotropic Glutamate)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02244-2


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[PMID]:29283228
[Au] Autor:Bazyan AS
[Ti] Título:Integration the Highest Function of Brain as the Basis of Cognition.
[So] Source:Usp Fiziol Nauk;47(3):17-29, 2016 Jul-Sep.
[Is] ISSN:0301-1798
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Based on the process needs, motivations and emotions, are describing molecular, cellular and systemic mechanisms of goal-direction motivated behavior. Goal-direction behavior is impossible without the orientation in space and forming a cognitive map. This process implements the hippocampus, via the neocortical connections. The hippocampus is linked to the amygdala, which is involved in the implementation of emotional behavior and organizing emotionally intense cognitive map or context of the environment.
[Mh] Termos MeSH primário: Tonsila do Cerebelo/fisiologia
Cognição/fisiologia
Emoções/fisiologia
Hipocampo/fisiologia
Rede Nervosa/fisiologia
[Mh] Termos MeSH secundário: Tonsila do Cerebelo/anatomia & histologia
Mapeamento Encefálico
Corpo Estriado/anatomia & histologia
Corpo Estriado/fisiologia
Hipocampo/anatomia & histologia
Seres Humanos
Motivação/fisiologia
Neocórtex/anatomia & histologia
Neocórtex/fisiologia
Rede Nervosa/anatomia & histologia
Plasticidade Neuronal/fisiologia
Receptores Dopaminérgicos/fisiologia
Receptores de GABA/fisiologia
Receptores de Glutamato Metabotrópico/fisiologia
Transdução de Sinais
Tálamo/anatomia & histologia
Tálamo/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Dopamine); 0 (Receptors, GABA); 0 (Receptors, Metabotropic Glutamate)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171229
[St] Status:MEDLINE


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[PMID]:29253887
[Au] Autor:Jensen R
[Ad] Endereço:Research Service, VA Boston Healthcare System, Boston, Massachusetts, United States of America.
[Ti] Título:Effects of GABACR and mGluR1 antagonists on contrast response functions of Sprague-Dawley and P23H rat retinal ganglion cells.
[So] Source:PLoS One;12(12):e0189980, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The GABACR antagonist TPMPA and the mGluR1 antagonist JNJ16259685 have been shown previously to alter the sensitivity of retinal ganglion cells (RGCs) in the Sprague-Dawley (SD) rat and P23H rat (animal model of retinitis pigmentosa) to brief flashes of light. In order to better understand the effects of these antagonists on the visual responses of SD and P23H rat RGCs, I examined the responses of RGCs to a drifting sinusoidal grating of various contrasts. Multielectrode array recordings were made from RGCs to a drifting sinusoidal grating of a spatial frequency of 1 cycle/mm and a temporal frequency of 2 cycles/s. In both SD and P23H rat retinas, contrast response functions were found to have a variable shape across cells. Some cells showed saturation of responses at high contrast levels while others did not. Whereas 49% of SD rat RGCs exhibited response saturation, only 14% of P23H rat RGCs showed response saturation. TPMPA decreased the responses of saturating SD rat RGCs to low (6% to 13%) grating contrasts but increased the response to the highest contrast (83%) tested. JNJ16259685 did not significantly affect the contrast response functions of either saturating or non-saturating SD rat RGCs. In contrast, both TPMPA and JNJ16259685 increased the responses of saturating and non-saturating P23H rat RGCs to all grating contrasts. Neither TPMPA nor JNJ16259685 affected the contrast thresholds of SD rat RGCs, but both antagonists lowered the contrast thresholds of P23H rat RGCs. Overall, the findings show that GABACR and mGluR1 antagonists have differential effects on the contrast response functions of SD and P23H rat RGCs. Notably, these receptor antagonists increase the responsiveness of P23H rat RGCs to both low and high contrast visual stimuli.
[Mh] Termos MeSH primário: Receptores de GABA/metabolismo
Receptores de Glutamato Metabotrópico/antagonistas & inibidores
Células Ganglionares da Retina/metabolismo
Retinite Pigmentosa/metabolismo
[Mh] Termos MeSH secundário: Animais
Comportamento Animal
Calibragem
Modelos Animais de Doenças
Eletrodos
Eletrofisiologia
Feminino
Homozigoto
Masculino
Ratos
Ratos Sprague-Dawley
Receptores de Glutamato Metabotrópico/metabolismo
Retina/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GABA-C receptor); 0 (Receptors, GABA); 0 (Receptors, Metabotropic Glutamate); 0 (metabotropic glutamate receptor type 1)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180112
[Lr] Data última revisão:
180112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189980


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[PMID]:29176838
[Au] Autor:Goniotaki D; Lakkaraju AKK; Shrivastava AN; Bakirci P; Sorce S; Senatore A; Marpakwar R; Hornemann S; Gasparini F; Triller A; Aguzzi A
[Ad] Endereço:Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
[Ti] Título:Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity.
[So] Source:PLoS Pathog;13(11):e1006733, 2017 Nov.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting the existence of deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form complexes with the cellular prion protein (PrPC), we investigated the impact of mGluR1 and mGluR5 inhibition on prion toxicity ex vivo and in vivo. We found that pharmacological inhibition of mGluR1 and mGluR5 antagonized dose-dependently the neurotoxicity triggered by prion infection and by prion-mimetic anti-PrPC antibodies in organotypic brain slices. Prion-mimetic antibodies increased mGluR5 clustering around dendritic spines, mimicking the toxicity of Aß oligomers. Oral treatment with the mGluR5 inhibitor, MPEP, delayed the onset of motor deficits and moderately prolonged survival of prion-infected mice. Although group-I mGluR inhibition was not curative, these results suggest that it may alleviate the neurological dysfunctions induced by prion diseases.
[Mh] Termos MeSH primário: Proteínas PrPC/toxicidade
Doenças Priônicas/tratamento farmacológico
Doenças Priônicas/metabolismo
Piridinas/administração & dosagem
Receptor de Glutamato Metabotrópico 5/metabolismo
Receptores de Glutamato Metabotrópico/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Anticorpos/administração & dosagem
Feminino
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Proteínas PrPC/genética
Proteínas PrPC/metabolismo
Doenças Priônicas/genética
Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores
Receptor de Glutamato Metabotrópico 5/genética
Receptores de Glutamato Metabotrópico/genética
Receptores de Glutamato Metabotrópico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (PrPC Proteins); 0 (Pyridines); 0 (Receptor, Metabotropic Glutamate 5); 0 (Receptors, Metabotropic Glutamate); 0 (metabotropic glutamate receptor type 1); 7VC0YVI27Y (6-methyl-2-(phenylethynyl)pyridine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006733


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[PMID]:29024663
[Au] Autor:Nasca C; Bigio B; Zelli D; de Angelis P; Lau T; Okamoto M; Soya H; Ni J; Brichta L; Greengard P; Neve RL; Lee FS; McEwen BS
[Ad] Endereço:Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA. Electronic address: cnasca@rockefeller.edu.
[Ti] Título:Role of the Astroglial Glutamate Exchanger xCT in Ventral Hippocampus in Resilience to Stress.
[So] Source:Neuron;96(2):402-413.e5, 2017 Oct 11.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27ac to regulate expression of xCT, which is also reduced in a genetic mouse model of inherent susceptibility to depressive-like behavior. Pharmacologically, modulating histone acetylation with acetyl-L-carnitine (LAC) or acetyl-N-cysteine (NAC) rapidly increases xCT and activates a network with mGlu2 receptors to prime an enhanced glutamate homeostasis that promotes both pro-resilient and antidepressant-like responses. Pharmacological xCT blockage counteracts NAC prophylactic effects. GFAP -Cre-dependent overexpression of xCT in vDG mimics pharmacological actions in promoting resilience. This work establishes a mechanism by which vDG protection leads to stress resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 network.
[Mh] Termos MeSH primário: Sistema y+ de Transporte de Aminoácidos/fisiologia
Astrócitos/fisiologia
Ácido Glutâmico/metabolismo
Hipocampo/fisiologia
Estresse Psicológico/metabolismo
[Mh] Termos MeSH secundário: Animais
Depressão/genética
Depressão/metabolismo
Depressão/psicologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Distribuição Aleatória
Receptores de Glutamato Metabotrópico/genética
Receptores de Glutamato Metabotrópico/metabolismo
Estresse Psicológico/genética
Estresse Psicológico/psicologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (Receptors, Metabotropic Glutamate); 0 (Slc7a11 protein, mouse); 0 (metabotropic glutamate receptor 2); 3KX376GY7L (Glutamic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE


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[PMID]:28886343
[Au] Autor:Watson LM; Bamber E; Schnekenberg RP; Williams J; Bettencourt C; Lickiss J; Jayawant S; Fawcett K; Clokie S; Wallis Y; Clouston P; Sims D; Houlden H; Becker EBE; Németh AH
[Ad] Endereço:Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
[Ti] Título:Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44.
[So] Source:Am J Hum Genet;101(3):451-458, 2017 Sep 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica/efeitos dos fármacos
Mutação de Sentido Incorreto/genética
Receptores de Glutamato Metabotrópico/genética
Ataxias Espinocerebelares/genética
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Antiparasitários/farmacologia
Feminino
Células HEK293
Seres Humanos
Masculino
Linhagem
Transdução de Sinais/efeitos dos fármacos
Ataxias Espinocerebelares/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiparasitic Agents); 0 (Receptors, Metabotropic Glutamate); 0 (Thiazoles); SOA12P041N (nitazoxanide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE


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[PMID]:28882644
[Au] Autor:Weon H; Kim TW; Youn DH
[Ad] Endereço:Department of Oral Physiology, BioCure Laboratory, School of Dentistry, Kyungpook National University, 2177 Dalgubeol Blvd, Jung-gu, Daegu 41940, Republic of Korea.
[Ti] Título:Postsynaptic N-type or P/Q-type calcium channels mediate long-term potentiation by group I metabotropic glutamate receptors in the trigeminal oralis.
[So] Source:Life Sci;188:110-117, 2017 Nov 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Both N-type and P/Q-type voltage-gated Ca channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs). MAIN METHODS: (S)-3,5-Dihydroxyphenylglycine (DHPG; 10µM for 5min), the group I mGluR agonist, was used to induce LTP of excitatory postsynaptic currents that were evoked in the Vo neurons by stimulating the trigeminal track. KEY FINDINGS: Weak blockade of the N-type or P/Q-type VGCCs by ω-conotoxin GVIA or ω-agatoxin IVA, respectively, which inhibited only 20-40% of Ca currents recorded in isolated trigeminal ganglion neurons but had no effect on the basal excitatory synaptic transmission, completely blocked the induction of LTP. In contrast, stronger blockade of the channels, which inhibited >50% of Ca currents and about 30% of basal synaptic transmission, resulted in the development of long-term depression (LTD), the long-lasting decrease of synaptic strength. Interestingly, the postsynaptic mechanism of DHPG-induced LTP, which was determined by paired-pulse ratio, disappeared when LTP was blocked, or LTD occurred, while a presynaptic mechanism still remained. SIGNIFICANCE: Our data suggest that postsynaptic N-type and P/Q-type VGCCs mediate the DHPG-induced LTP at the trigeminal afferent synapses in the Vo.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo N/fisiologia
Canais de Cálcio Tipo P/fisiologia
Canais de Cálcio Tipo Q/fisiologia
Potenciação de Longa Duração/fisiologia
Receptores de Glutamato Metabotrópico/fisiologia
Núcleo Espinal do Trigêmeo/fisiologia
[Mh] Termos MeSH secundário: Agatoxinas/farmacologia
Animais
Agonistas dos Canais de Cálcio/farmacologia
Bloqueadores dos Canais de Cálcio
Cromonas/farmacologia
Feminino
Potenciação de Longa Duração/efeitos dos fármacos
Depressão Sináptica de Longo Prazo/efeitos dos fármacos
Depressão Sináptica de Longo Prazo/fisiologia
Masculino
Terminações Pré-Sinápticas/fisiologia
Ratos
Receptores de Glutamato Metabotrópico/agonistas
Potenciais Sinápticos/fisiologia
Transmissão Sináptica/efeitos dos fármacos
Núcleo Espinal do Trigêmeo/efeitos dos fármacos
ômega-Conotoxinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((S)-3,7-dihydroxychroman-4-one); 0 (Agatoxins); 0 (Calcium Channel Agonists); 0 (Calcium Channel Blockers); 0 (Calcium Channels, N-Type); 0 (Calcium Channels, P-Type); 0 (Calcium Channels, Q-Type); 0 (Chromones); 0 (Receptors, Metabotropic Glutamate); 0 (omega-Conotoxins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE


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[PMID]:28772121
[Au] Autor:Thomson SR; Seo SS; Barnes SA; Louros SR; Muscas M; Dando O; Kirby C; Wyllie DJA; Hardingham GE; Kind PC; Osterweil EK
[Ad] Endereço:Centre for Integrative Physiology/Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
[Ti] Título:Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.
[So] Source:Neuron;95(3):550-563.e5, 2017 Aug 02.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu ) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1 ) hippocampus, which exhibit exaggerated mGlu -induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M ) is excessively translated, and synthesis of M downstream of mGlu activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M activity normalizes core phenotypes in the Fmr1 , including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1 brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain.
[Mh] Termos MeSH primário: Proteína do X Frágil de Retardo Mental/metabolismo
Síndrome do Cromossomo X Frágil/tratamento farmacológico
Hipocampo/citologia
Depressão Sináptica de Longo Prazo/fisiologia
Neurônios/citologia
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Proteína do X Frágil de Retardo Mental/genética
Síndrome do Cromossomo X Frágil/genética
Síndrome do Cromossomo X Frágil/metabolismo
Metoxi-Hidroxifenilglicol/farmacologia
Camundongos Transgênicos
Biossíntese de Proteínas/efeitos dos fármacos
Receptores de Glutamato Metabotrópico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Metabotropic Glutamate); 139135-51-6 (Fragile X Mental Retardation Protein); 534-82-7 (Methoxyhydroxyphenylglycol)
[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:170804
[St] Status:MEDLINE


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[PMID]:28704052
[Au] Autor:Doornbos MLJ; Cid JM; Haubrich J; Nunes A; van de Sande JW; Vermond SC; Mulder-Krieger T; Trabanco AA; Ahnaou A; Drinkenburg WH; Lavreysen H; Heitman LH; IJzerman AP; Tresadern G
[Ad] Endereço:Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University , P.O. Box 9502, 2300RA Leiden, The Netherlands.
[Ti] Título:Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2.
[So] Source:J Med Chem;60(15):6704-6720, 2017 Aug 10.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k , k and residence time (RT) were determined. The PAMs showed various kinetic profiles; k values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu PAMs with high values for k but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.
[Mh] Termos MeSH primário: Agonistas de Aminoácidos Excitatórios/farmacologia
Piridinas/farmacologia
Receptores de Glutamato Metabotrópico/agonistas
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Regulação Alostérica
Animais
Células CHO
Cricetulus
Agonistas de Aminoácidos Excitatórios/síntese química
Cinética
Piperidinas/farmacologia
Piridinas/síntese química
Ratos Sprague-Dawley
Sono REM/efeitos dos fármacos
Relação Estrutura-Atividade
Triazóis/síntese química
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(cyclopropylmethyl)-7-((4-phenyl-1-piperidinyl)methyl)-8-(trifluoromethyl)-1,2,4-triazolo(4,3-a)pyridine); 0 (Excitatory Amino Acid Agonists); 0 (Piperidines); 0 (Pyridines); 0 (Receptors, Metabotropic Glutamate); 0 (Triazoles); 0 (metabotropic glutamate receptor 2); 10028-17-8 (Tritium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00669



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