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1.
Nat Commun ; 14(1): 7941, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38040676

RESUMO

Steranes preserved in sedimentary rocks serve as molecular fossils, which are thought to record the expansion of eukaryote life through the Neoproterozoic Era ( ~ 1000-541 Ma). Scientists hypothesize that ancient C27 steranes originated from cholesterol, the major sterol produced by living red algae and animals. Similarly, C28 and C29 steranes are thought to be derived from the sterols of prehistoric fungi, green algae, and other microbial eukaryotes. However, recent work on annelid worms-an advanced group of eumetazoan animals-shows that they are also capable of producing C28 and C29 sterols. In this paper, we explore the evolutionary history of the 24-C sterol methyltransferase (smt) gene in animals, which is required to make C28+ sterols. We find evidence that the smt gene was vertically inherited through animals, suggesting early eumetazoans were capable of C28+ sterol synthesis. Our molecular clock of the animal smt gene demonstrates that its diversification coincides with the rise of C28 and C29 steranes in the Neoproterozoic. This study supports the hypothesis that early eumetazoans were capable of making C28+ sterols and that many animal lineages independently abandoned its biosynthesis around the end-Neoproterozoic, coinciding with the rise of abundant eukaryotic prey.


Assuntos
Fitosteróis , Rodófitas , Animais , Esteróis , Evolução Biológica , Fósseis
2.
PLoS One ; 13(9): e0204227, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30248121

RESUMO

AIMS: The cognitive profile of Myotonic Dystrophy type 1 (DM1) has been described in recent decades. Moreover, DM1 patients show lowered social engagement and difficulties in social-cognitive functions. The aim of the present study is to explore whether social cognition impairment is present in DM1 taking into account the overall cognitive condition. METHOD: 38 patients and a control group paired in age and gender participated in the study. All the participants had an IQ within the normal range. Subjects were administered an abbreviated neuropsychological battery which comprised a facial emotion recognition test (POFA) and Faux Pas Test, as well as a self-report questionnaire on cognitive and affective empathy (TECA). RESULTS: Statistically significant differences were found only for facial emotion recognition (U = 464.0, p = .006) with a moderate effect size (.31), with the controls obtaining a higher score than the patients. Analyzing each emotion separately, DM1 patients scored significantly lower than controls on the recognition of anger and disgust items. Emotion recognition did not correlate with genetic load, but did correlate negatively with age. No differences were found between patients and controls in any of the other variables related to Theory of Mind (ToM) and empathy. CONCLUSION: DM1 does not manifest specific impairments in ToM since difficulties in this area predominantly rely on the cognitive demand of the tasks employed. However, a more basic process such as emotion recognition appears as a core deficit. The role of this deficit as a marker of aging related decline is discussed.


Assuntos
Cognição , Distrofia Miotônica/psicologia , Adulto , Fatores Etários , Estudos de Casos e Controles , Emoções , Empatia , Reconhecimento Facial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Autorrelato , Comportamento Social
3.
Rev Neurol ; 65(5): 216-222, 2017 Sep 01.
Artigo em Espanhol | MEDLINE | ID: mdl-28849863

RESUMO

INTRODUCTION: Being a woman increases the risk of developing multiple sclerosis, an illness where biopsychosocial factors (psychological stress, perceived social support, psychological well-being, coping strategies) may have a clinical impact. AIMS: To assess how stress management is affected in remitting-relapsing multiple sclerosis and to analyze gender differences both in terms of stress management and patients' cognitive performance. PATIENTS AND METHODS: 42 patients were neuropsychologically evaluated with the Brief Repeatable Battery of Neuropsychological Tests, four psychosocial questionnaires and Beck's Depression Inventory. Two main analyses were conducted: mean comparisons between men and women for clinical, neuropsychological and psychosocial variables, and a correlation analysis between the psychosocial and clinical variables of the illness in the whole sample, as well as in men and women separately. RESULTS: Men and women showed differences in the outbreak rate and in the attention/executive function domain. The correlation analysis revealed that the strongest correlation was between clinical and psychosocial variables when the group was divided according to gender. Any predominant coping strategy was not detected in the multiple sclerosis group, but it was observed that women had an increased tendency to self-incriminate. CONCLUSION: This study emphasizes the importance of assessing these remitting-relapsing multiple sclerosis patients both cognitively and psychosocially, differentiating them by gender.


TITLE: Factores psicosociales y rendimiento cognitivo en esclerosis multiple: diferencias de sexo.Introduccion. Ser mujer aumenta el riesgo de padecer esclerosis multiple, enfermedad sobre la que diversos factores biopsicosociales (estres psicologico, apoyo social percibido, bienestar psicologico, estrategias de afrontamiento) pueden tener un impacto clinico. Objetivo. Valorar como afecta el manejo del estres en la esclerosis multiple remitente recurrente y analizar las diferencias de sexo tanto en el manejo del estres como en el rendimiento cognitivo de los pacientes. Pacientes y metodos. Se evaluo neuropsicologicamente a 42 pacientes mediante la Brief Repeatable Battery of Neuropsychological Tests, cuatro cuestionarios psicosociales y el inventario de depresion de Beck. Se realizaron dos analisis principales: comparacion de medias entre hombres y mujeres para variables clinicas, neuropsicologicas y psicosociales, y analisis de correlacion entre variables psicosociales y clinicas de la enfermedad tanto en la muestra en su conjunto como con las submuestras de hombres y mujeres. Resultados. Hombres y mujeres obtuvieron diferencias en tasa de brote y el rendimiento en el dominio atencion/funciones ejecutivas. Los analisis de correlacion mostraron un mayor peso de la relacion entre las variables clinicas y psicosociales cuando se dividio el grupo por sexos. No se ha detectado un estilo de estrategia de afrontamiento predominante en la esclerosis multiple, pero si se ha visto que las mujeres tienen mayor tendencia a autoinculparse. Conclusion. Este estudio destaca la importancia de estudiar cognitiva y psicosocialmente la esclerosis multiple remitente recurrente, diferenciandola por sexo.


Assuntos
Cognição , Esclerose Múltipla/complicações , Esclerose Múltipla/psicologia , Estresse Psicológico/etiologia , Adulto , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Fatores Sexuais
4.
Oral Oncol ; 70: 65-72, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28427762

RESUMO

Head and neck cancer is one of the most frequent malignances worldwide. Despite the site-specific multimodality therapy, up to half of the patients will develop recurrence. Treatment selection based on a multidisciplinary tumor board represents the cornerstone of head and neck cancer, as it is essential for achieving the best results, not only in terms of outcome, but also in terms of organ-function preservation and quality of life. Evidence-based international and national clinical practice guidelines for head and neck cancer not always provide answers in terms of decision-making that specialists have to deal with in their daily practice. This is the first Expert Consensus on the Multidisciplinary Approach for Head and Neck Squamous Cell Carcinoma (HNSCC) elaborated by the Spanish Society for Head and Neck Cancer and based on a Delphi methodology. It offers a number of specific recommendations based on the available evidence and the expertise of our specialists to facilitate decision-making of all health-care specialists involved.


Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas/patologia , Terapia Combinada , Consenso , Técnica Delphi , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Espanha , Carcinoma de Células Escamosas de Cabeça e Pescoço
5.
Comput Biol Med ; 41(8): 600-10, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21621760

RESUMO

Dementia is a growing concern due to the aging process of the western societies. Non-invasive detection is therefore a high priority research endeavor. In this paper we report results of classification systems applied to the feature vectors obtained by a feature extraction method computed on structural magnetic resonance imaging (sMRI) volumes for the detection of two neurological disorders with cognitive impairment: myotonic dystrophy of type 1 (MD1) and Alzheimer disease (AD). The feature extraction process is based on the voxel clusters detected by voxel-based morphometry (VBM) analysis of sMRI upon a set of patient and control subjects. This feature extraction process is specific for each kind of disease and is grounded on the findings obtained by medical experts. The 10-fold cross-validation results of several statistical and neural network based classification algorithms trained and tested on these features show high specificity and moderate sensitivity of the classifiers, suggesting that the approach is better suited for rejecting than for detecting early stages of the diseases.


Assuntos
Algoritmos , Doença de Alzheimer/patologia , Encéfalo/patologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Distrofia Miotônica/patologia , Adulto , Doença de Alzheimer/diagnóstico , Análise por Conglomerados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/diagnóstico , Redes Neurais de Computação , Reprodutibilidade dos Testes
6.
Biochim Biophys Acta ; 1812(7): 732-42, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21439371

RESUMO

Tau is the proteinaceous component of intraneuronal aggregates common to neurodegenerative diseases called Tauopathies, including myotonic dystrophy type 1. In myotonic dystrophy type 1, the presence of microtubule-associated protein Tau aggregates is associated with a mis-splicing of Tau. A toxic gain-of-function at the ribonucleic acid level is a major etiological factor responsible for the mis-splicing of several transcripts in myotonic dystrophy type 1. These are probably the consequence of a loss of muscleblind-like 1 (MBNL1) function or gain of CUGBP1 and ETR3-like factor 1 (CELF1) splicing function. Whether these two dysfunctions occur together or separately and whether all mis-splicing events in myotonic dystrophy type 1 brain result from one or both of these dysfunctions remains unknown. Here, we analyzed the splicing of Tau exons 2 and 10 in the brain of myotonic dystrophy type 1 patients. Two myotonic dystrophy type 1 patients showed a mis-splicing of exon 10 whereas exon 2-inclusion was reduced in all myotonic dystrophy type 1 patients. In order to determine the potential factors responsible for exon 10 mis-splicing, we studied the effect of the splicing factors muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1), CUGBP1 and ETR3-like factor 2 (CELF2), and CUGBP1 and ETR3-like factor 4 (CELF4) or a dominant-negative CUGBP1 and ETR-3 like factor (CELF) factor on Tau exon 10 splicing by ectopic expression or siRNA. Interestingly, the inclusion of Tau exon 10 is reduced by CUGBP1 and ETR3-like factor 2 (CELF2) whereas it is insensitive to the loss-of-function of muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1) gain-of-function, or a dominant-negative of CUGBP1 and ETR-3 like factor (CELF) factor. Moreover, we observed an increased expression of CUGBP1 and ETR3-like factor 2 (CELF2) only in the brain of myotonic dystrophy type 1 patients with a mis-splicing of exon 10. Taken together, our results indicate the occurrence of a mis-splicing event in myotonic dystrophy type 1 that is induced neither by a loss of muscleblind-like 1 (MBNL1) function nor by a gain of CUGBP1 and ETR3-like factor 1 (CELF1) function but is rather associated to CUGBP1 and ETR3-like factor 2 (CELF2) gain-of-function.


Assuntos
Éxons , Inativação Gênica , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA/genética , Proteínas tau/genética , Sequência de Bases , Encéfalo/metabolismo , Proteínas CELF , Primers do DNA , Humanos , Distrofia Miotônica/genética , Distrofia Miotônica/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas tau/metabolismo
7.
Psychol Med ; 40(3): 487-95, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19627641

RESUMO

BACKGROUND: Although central nervous system (CNS) involvement in adult myotonic dystrophy type 1 (DM1) was described long ago, the large number of variables affecting the cognitive and personality profile have made it difficult to determine the effect of DM1 on the brain. The aim of this study was to define the cognitive and personality patterns in adult DM1 patients, and to analyse the relationship between these clinical patterns and their association with the underlying molecular defect. METHOD: We examined 121 adult DM1 patients with confirmed molecular CTG repeat expansion and 54 control subjects using comprehensive neuropsychological tests and personality assessments with the Millon Clinical Multiaxial Inventory (MCMI)-II. We used a multiple linear regression model to assess the effect of each variable on cognition and personality adjusted to the remainders. RESULTS: Patients performed significantly worse than controls in tests measuring executive function (principally cognitive inflexibility) and visuoconstructive ability. In the personality profile, some paranoid and aggressive traits were predominant. Furthermore, there was a significant negative correlation between the CTG expansion size and many of the neuropsychological and personality measures. The molecular defect also correlated with patients' daytime somnolence. CONCLUSIONS: Besides muscular symptomatology, there is significant CTG-dependent involvement of the CNS in adult DM1 patients. Our data indicate that the cognitive impairment predominantly affects the fronto-parietal lobe.


Assuntos
Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/psicologia , Distrofia Miotônica/epidemiologia , Distrofia Miotônica/psicologia , Personalidade , Expansão das Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Idoso , Análise de Variância , Southern Blotting/métodos , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/genética , Miotonina Proteína Quinase , Testes Neuropsicológicos/estatística & dados numéricos , Inventário de Personalidade/estatística & dados numéricos , Reação em Cadeia da Polimerase/métodos , Proteínas Serina-Treonina Quinases/genética , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Sequências Repetitivas de Ácido Nucleico , Espanha/epidemiologia , Adulto Jovem
8.
Genes Brain Behav ; 8(1): 53-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18823405

RESUMO

Previous studies based on case descriptions and neuroradiological findings have suggested central nervous system (CNS) involvement in facioscapulohumeral dystrophy. The aim of this work is to explore the relationship between cognitive/personality pattern and the underlying molecular defect for this muscular dystrophy. We performed a wide-ranging neuropsychological assessment of 34 molecularly confirmed facioscapulohumeral dystrophy patients and 49 control subjects, all of whom also received the Millon-II Multiaxial Clinical Inventory (MCMI-II). Patients and controls show mild learning-level differences in the neuropsychological profile, and only the hysteriform scale is statistically higher in patients than controls. The patients' intelligence quotient (IQ) is related to the size of the deleted fragment but not to the degree of muscular impairment. The results of this study indicate a cut-off point and two distinct cognitive profiles in facioscapulohumeral dystrophy, depending on the patients' molecular defect: patients with a fragment size > 24 kb show a relatively normal cognitive pattern, whereas those with a fragment size < or = 24 kb show a significantly reduced IQ and difficulties with verbal function and visuo-constructive tasks. This work provides more evidence for the involvement of the CNS in facioscapulohumeral dystrophy and suggests that the fragment size should be taken into account in the clinical management of facioscapulohumeral dystrophy as it has a predictive value on the cognitive phenotype.


Assuntos
Distrofias Musculares/genética , Distrofias Musculares/psicologia , Adolescente , Adulto , Idoso , Cognição/fisiologia , DNA/genética , Desoxirribonuclease EcoRI/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Inteligência/genética , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Personalidade/fisiologia , Testes de Personalidade , Fenótipo , Análise de Regressão , Aprendizagem Verbal , Escalas de Wechsler , Adulto Jovem
9.
Neurobiol Aging ; 28(12): 1941-3, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17011669

RESUMO

Alzheimer's disease (AD) is the most common dementing disorder and presents with a progressive and irreversible cognitive decline of gradual onset. To date, several reports have involved iron in AD physiopathology. In this study, we have analysed TFC2 variant and HFE mutations (H63D and C282Y) in 211 AD patients and 167 controls recruited from an area of the Basque Country. Furthermore, we have studied APOE genotype as it is a well-known risk factor for AD. APOE epsilon 4 allele was associated with an increased risk of AD and an earlier age at onset, whereas no association was found between TFC2 or HFE C282Y mutation and disease susceptibility. The frequency of H63D mutation was higher in control population (29.9%) than in AD patients (18%), suggesting a protective role of this allele on AD either due to the presence of the mutation itself or through the effect of other related genes in the ancestral haplotype in which it is included.


Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Antígenos de Histocompatibilidade Classe I/genética , Distúrbios do Metabolismo do Ferro/epidemiologia , Distúrbios do Metabolismo do Ferro/genética , Proteínas de Membrana/genética , Medição de Risco/métodos , Transferrina/genética , Idoso , Comorbidade , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Proteína da Hemocromatose , Humanos , Masculino , Prevalência , Fatores de Risco , Espanha/epidemiologia
10.
J Neurochem ; 75(4): 1566-74, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10987837

RESUMO

We have addressed the role of protein phosphatases (PPs) in the modulation of the switch in glutamate release observed after repetitive stimulation of group I metabotropic glutamate receptors (mGluRs). In cerebrocortical nerve terminals the agonist (S:)-3, 5-dihydroxyphenylglycine facilitated evoked glutamate release. However, a second stimulation, 5 min later, reduced rather than facilitated this release. This switch in the control of glutamate release was reversed when a 30-min interval was left between stimulations. Inhibition of the endogenous PPs, PP1 and PP2A, with calyculin A and okadaic acid prevented the recovery of the facilitatory response and maintained the receptor permanently coupled to the inhibitory pathway. The inhibitors of PP2B, cyclosporin A and cypermethrine, had no effect. The inhibition of glutamate release was insensitive to pertussis toxin and was the result of the loss of the release component coupled to N-type Ca(2+) channels. This inhibitory action was suppressed by addition of the protein kinase C activator 4beta-phorbol 12,13-dibutyrate. We conclude that the balance between protein kinase and phosphatase activity at the nerve terminal plays a key role in accommodating the modulation of glutamate release by group I mGluRs.


Assuntos
Ácido Glutâmico/metabolismo , Glicina/análogos & derivados , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais , Sinaptossomos/metabolismo , 4-Aminopiridina/farmacologia , Animais , Química Encefálica , Canais de Cálcio Tipo N/efeitos dos fármacos , Canais de Cálcio Tipo N/metabolismo , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Glicina/farmacologia , Masculino , Toxina Pertussis , Dibutirato de 12,13-Forbol/farmacologia , Potássio/farmacologia , Bloqueadores dos Canais de Potássio , Proteína Quinase C/metabolismo , Proteína Fosfatase 1 , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/agonistas , Resorcinóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Fatores de Virulência de Bordetella/farmacologia
11.
Neuropharmacology ; 39(9): 1544-53, 2000 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-10854899

RESUMO

We have addressed the role of arachidonic acid in the facilitation of glutamate release by group I metabotropic glutamate (mGlu) receptors. The activation of these receptors with the specific agonist 3,5-dihydroxyphenylglycine (DHPG) failed to enhance the cumulative Ca(2+)-dependent release of glutamate evoked by a 5 min depolarization with 4-aminopyridine, in the absence but not in the presence of arachidonic acid. However, DHPG, in the absence of arachidonic acid, transiently enhanced diacylglycerol levels, transiently potentiated 4AP-evoked depolarization, and significantly enhanced the fast but not the slow component of glutamate release observed after prolonged stimulations of nerve terminals. Further evidence that DHPG was able to initiate release facilitation in the absence of arachidonic acid was obtained in experiments where the protein phosphatase 2B (cyclosporine A and cypermethrine) but not protein phosphatase 1 or 2A inhibitors (okadaic acid and calyculin A) facilited glutamate release to a maximal extent comparable to that induced by arachidonic acid. We conclude that an active protein phosphatase 2B (calcineurin) dephosphorylates the presynaptic target/s responsible for facilitation of glutamate release.


Assuntos
Ácido Araquidônico/farmacologia , Inibidores de Calcineurina , Ácido Glutâmico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , 4-Aminopiridina/farmacologia , Animais , Calcineurina/metabolismo , Cálcio/metabolismo , Cálcio/farmacologia , Ciclosporina/farmacologia , Diglicerídeos/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Glicina/análogos & derivados , Glicina/farmacologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Proteína Fosfatase 1 , Piretrinas/farmacologia , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/fisiologia , Resorcinóis/farmacologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/fisiologia , Fatores de Tempo
12.
Neuropharmacology ; 37(12): 1485-92, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9886671

RESUMO

In this study we have addressed the identification of the metabotropic glutamate receptor (mGluR) involved in the facilitation of glutamate release in nerve terminals from the cerebral cortex. mGluR1 and 5 are coupled to phosphoinositide hydrolysis and the activation of these receptors with the specific agonist 3,5-dihydroxyphenylglycine (DHPG) enhances the release of glutamate. We have examined whether mGluR1 is responsible for this modulatory effect by preparing nerve terminals from mGluR 1 deficient mice. The Ca2+-dependent glutamate release evoked by a submaximal depolarization is enhanced by the agonist DHPG in nerve terminals from both wild and mutant mice. This result is consistent with the finding that the mGluR agonist also induces a similar increase in the levels of diacylglycerol (DAG) in the nerve terminals from wild and mutant mice. Moreover, the activity-dependent switch from facilitation to inhibition of release, observed when a second stimulation of the receptor is applied shortly after (5 min) the first pulse, was also observed in the mutant mice. These results indicate therefore, that the facilitation of glutamate release is unlikely to be due to the activation of mGluR1 but related to another phosphoinositide coupled mGluR.


Assuntos
Córtex Cerebral/metabolismo , Ácido Glutâmico/metabolismo , Terminações Nervosas/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Diglicerídeos/metabolismo , Glicina/análogos & derivados , Glicina/farmacologia , Camundongos , Camundongos Knockout , Fosfatidilinositóis/metabolismo , Agonistas do Receptor Purinérgico P1 , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/deficiência , Receptores de Glutamato Metabotrópico/genética , Valores de Referência , Resorcinóis/farmacologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Fatores de Tempo
13.
Neuron ; 21(6): 1477-86, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9883739

RESUMO

We have explored whether the desensitization of metabotropic glutamate receptors (mGluRs) coupled to phosphoinositide hydrolysis affects the role that they play in modulating glutamate release. In hippocampal nerve terminals, the agonist 3,5-dihydroxyphenylglycine (DHPG) facilitated evoked glutamate release, but a second stimulation 5 min later reduced rather than facilitated release. After a 30 min interval between stimulations, DHPG again facilitated glutamate release. In hippocampal slices, DHPG caused an inhibition of excitatory postsynaptic currents (EPSCs) recorded from CA1 neurons. However, when the effects of ambient glutamate were prevented, mGluR activation initially induced a facilitation of synaptic transmission, followed by an inhibition. We conclude that group I mGluRs have a dual action on glutamate release, switching from facilitatory to inhibitory upon receptor desensitization triggered by low concentrations of glutamate.


Assuntos
Hipocampo/fisiologia , Terminações Nervosas/fisiologia , Neurônios/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Transmissão Sináptica/fisiologia , Sinaptossomos/fisiologia , Animais , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Ácido Glutâmico/farmacologia , Ácido Glutâmico/fisiologia , Glicina/análogos & derivados , Glicina/farmacologia , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Modelos Neurológicos , Terminações Nervosas/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Resorcinóis/farmacologia , Sinaptossomos/efeitos dos fármacos
14.
Eur J Pharmacol ; 321(2): 247-57, 1997 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-9063695

RESUMO

The mechanism by which changes in cyclic GMP (cGMP) regulate glutamate release was investigated in rat cerebrocortical nerve terminals. The elevation of cGMP levels by inhibition of cGMP-phosphodiesterase with 2-o-propoxy-phenyl-8-azapurin-6-one (zaprinast) reduced the Ca(2+)-dependent glutamate release evoked by depolarization with 30 mM KCl or 1 mM 4-aminopyridine. The nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine also enhanced cGMP and reduced glutamate release. In addition, the membrane-permeable analogs 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP) and N,2'-o-dibutyrylguanosine (dbcGMP) at 10 microM also mimic glutamate release inhibition. The reduction in glutamate release was observed with no modifications in the ATP/ADP ratio, and was reversed in the presence of the protein kinases inhibitor [N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide, HCl] (H-8). Interestingly, higher concentrations of dbcGMP (1 mM) abolished the inhibition observed with low concentrations although no facilitation was observed. This finding seems to indicate the existence of a dual role for cGMP in the control of glutamate exocytosis.


Assuntos
GMP Cíclico/fisiologia , Ácido Glutâmico/metabolismo , Óxido Nítrico/fisiologia , Transdução de Sinais/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , GMP Cíclico/biossíntese , Ativação Enzimática/efeitos dos fármacos , Exocitose/efeitos dos fármacos , Guanilato Ciclase/metabolismo , Masculino , Terminações Nervosas/metabolismo , Terminações Nervosas/fisiologia , Inibidores de Fosfodiesterase/farmacologia , Proteínas Quinases/fisiologia , Purinonas/farmacologia , Ratos , Ratos Wistar , Sinaptossomos/metabolismo
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