589 results on '"J. Bockaert"'
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2. Characteristics of Serotonin Receptors in the Rat Brain
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D. L. Nelson, J. Glowinski, J. Bockaert, A. Herbet, and M. Hamon
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Agonist ,medicine.medical_specialty ,medicine.drug_class ,Chemistry ,Quipazine ,Adenylate kinase ,Cyclase ,Endocrinology ,Internal medicine ,medicine ,Binding site ,Receptor ,Cyclase activity ,5-HT receptor ,medicine.drug - Abstract
Two biochemical methods are currently available for studying 5-HT receptors in the central nervous system. The first consists of measuring the specific high affinity binding of 3H-5-HT to synaptic membranes. The other derives from the discovery of an adenylate cyclase which can be activated by 5-HT in brain homogenates. Whereas the specific 3H-5-HT binding is measurable in young as well as in adult rats, the 5-HT-sensitive adenylate cyclase can be quantitatively estimated only during the first three weeks following birth. Later on, the increment of adenylate cyclase activity produced by 5-HT is too low to permit valid measurements, notably in tissues from adult rats. Studies on the effects of various agonists and antagonists demonstrated that the specific binding site characterized by a high affinity for 3H-5-HT (Kd = 1.5 nM) exhibited the expected properties of a 5-HT receptor in brain. Performing chemical lesions on serotoninergic neurons by an intracerebral injection of 5, 7-dihydroxytryptamine or the blockade of central 5-HT receptors by the peripheral administration of methiothepin resulted in a subsequent increase in the number of specific binding sites for 3H-5-HT particularly in the hippocampus (+30 to +45%). In contrast, preliminary attempts to detect any supersensitivity of the 5-HT-sensitive adenylate cyclase after selective raphe lesions were unsuccessful. Indeed, several observations strongly suggested that the high affinity binding site for 3H-5-HT did not correspond to the 5-HT receptor coupled to adenylate cyclase in synaptic membranes: 1) the apparent affinity of the 5-HT-sensitive adenylate cyclase for 5-HT was about 300 times lower (Kd = 0.5 microM) than that of the specific 3H-5-HT binding site; 2)the ontogenic evolutions of 3H-5-HT binding and 5-HT-sensitive adenylate cyclase were not parallel, notably in the hippocampus; 3) they were differently affected by several drugs. For instance, quipazine, a putative 5-HT agonist, effectively displaced 3H-5-HT from its specific binding site (Ki = 0.23 microM) whereas it did not affect 5-HT-sensitive adenylate cyclase. In conclusion, it is likely that the high affinity binding site for 3H-5-HT and the 5-HT-sensitive adenylate cyclase belong to two different postsynaptic 5-HT receptors in the rat brain.
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- 2015
3. Introduction
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J. Bousquet, R. Bourret, T. Camuzat, P. Augé, P. Domy, J. Bringer, N. Best, O. Jonquet, J.-E. de la Coussaye, M. Noguès, J.-M. Robine, A. Avignon, H. Blain, B. Combe, G. Dray, V. Dufour, M. Fouletier, N. Giraudeau, D. Hève, C. Jeandel, I. Laffont, D. Larrey, D. Laune, C. Laurent, P. Mares, C. Marion, E. Pastor, J.-Y. Pélissier, F. Radier-Pontal, J. Reynes, E. Royère, M. Ychou, A. Bedbrook, S. Granier, F. Abecassis, S. Albert, P.-A. Adnet, B. Alomène, M. Amouyal, S. Arnavielhe, T. Asteriou, V. Attalin, P. Aubas, C. Azevedo, M. Badin, null Bakhti, G. Baptista, B. Bardy, M.-P. Battesti, O. Bénézet, P.-L. Bernard, C. Berr, J. Berthe, X. Bobia, J. Bockaert, C. Boegner, S. Boichot, H.-Y. Bonnin, P. Boulet, S. Bouly, C. Boubakri, A. Bourdin, J.-L. Bourrain, G. Bourrel, V. Bouix, C. Breuker, V. Bruguière, J. Burille, S. Cade, D. Caimmi, M.-V. Calmels, W. Camu, G. Canovas, V. Carre, G. Cavalli, G. Cayla, R. Chiron, P.-G. Claret, P. Coignard, F. Coroian, D.-J. Costa, P. Costa, null Cottalorda, B. Coulet, A.-L. Coupet, M.-C. Courrouy-Michel, P. Courtet, J.-P. Cristol, V. Cros, F. Cuisinier, C. Daien, M. Danko, P. Dauenhauer, M. Dauzat, M. David, J.-M. Davy, D. Delignières, P. Demoly, J. Desplan, H. Dhivert-Donnadieu, P. Dujols, A. Dupeyron, G. Dupeyron, O. Engberink, M. Enjalbert, C. Fattal, J. Fernandes, P. Fesler, P. Fraisse, J. Froger, P. Gabrion, E. Galano, M. Gellerat-Rogier, A. Gellis, A.-Y. Goucham, F. Gouzi, F. Gressard, J.-C. Gris, B. Guillot, D. Guiraud, V. Handweiler, H. Hantkié, M. Hayot, C. Hérisson, C. Heroum, D. Hoa, S. Jacquemin, S. Jaber, D. Jakovenko, C. Jorgensen, L. Journot, M. Kaczorek, P. Kouyoudjian, P. Labauge, L. Landreau, M. Lapierre, C. Leblond, M.-S. Léglise, J.-M. Lemaitre, V. Le Moing, A. Le Quellec, F. Leclercq, S. Lehmann, B. Lognos, J.-M. Lussert, A. Makinson, K. Mandrick, V. Marmelat, P. Martin-Gousset, A. Matheron, G. Mathieu, M. Meissonnier, G. Mercier, P. Messner, C. Meunier, M. Mondain, R. Morales, J. Morel, D. Morquin, D. Mottet, P. Nérin, P. Nicolas, G. Ninot, F. Nouvel, J.-P. Ortiz, D. Paccard, G. Pandraud, M.-P. Pasdelou, J.-L. Pasquié, K. Patte, S. Perrey, Y.-M. Pers, M.-C. Picot, J.-P. Pin, N. Pinto, E. Porte, F. Portejoie, J.-L. Pujol, X. Quantin, I. Quéré, N. Raffort, S. Ramdani, J. Ribstein, I. Rédini-Martinez, S. Richard, K. Ritchie, J.-P. Riso, F. Rivier, C. Rolland, F. Roubille, D. Sablot, J.-L. Savy, L. Schifano, P. Senesse, R. Sicard, B. Soua, Y. Stephan, D. Strubel, A. Sultan, null Taddei-Ologeanu, G. Tallon, M. Tanfin, H. Tassery, I. Tavares, K. Torre, J. Touchon, V. Tribout, A. Uziel, P. Van de Perre, X. Vasquez, J.-M. Verdier, C. Vergne-Richard, G. Vergotte, L. Vian, C. Viarouge-Reunier, F. Vialla, F. Viart, M. Villain, M. Villiet, E. Viollet, A. Wojtusciszyn, M. Aoustin, C. Bourquin, J. Mercier, Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Région Languedoc-Roussillon-Midi-Pyrénées, Centre de pharmacologie et innovation dans le diabète (CPID), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre National de la Recherche Scientifique (CNRS), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Geriatrics - Efficiency and Deficiency Laboratory, Hôpital Lapeyronie [Montpellier] (CHU), Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Euromov (EuroMov), Université de Montpellier (UM), Hôpital Saint Eloi (CHRU Montpellier), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre d'Estudis del Risc Tecnològic, Universitat Politècnica de Catalunya [Barcelona] (UPC), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Laboratorium für Physikalische Chemie (ETH-LPC), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Kyomed, Montpellier Research in Management (MRM), Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), ONERA - The French Aerospace Lab [Lille], ONERA, Institut de Génomique Fonctionnelle (IGF), Société Publique Locale d'Exploitation de Balaruc-les-Bains, Balaruc-Les-Bains, Chimie, biologie et radicaux libres - UMR 6517 (CBRL), Université de la Méditerranée - Aix-Marseille 2-Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Département de dermatologie [CHU de Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Médecine interne, maladies multi-organiques de l'adulte [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Aix-Marseille Université - Faculté des Sciences du Sport (AMU FSS), Aix Marseille Université (AMU), Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Département Médecine interne, Hôpital Lapeyronie, Agence Régionale de la Santé (ARS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de magnétisme et d'optique de Versailles (LMOV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), GEOMAR LEGOS, Laboratoire d'études en Géophysique et océanographie spatiales (LEGOS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), CHU Saint-Eloi, Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,030212 general & internal medicine ,General Medicine ,ComputingMilieux_MISCELLANEOUS ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience
- Published
- 2015
4. HET SYNDROOM VAN LEMIERRE: EEN GECOMPLICEERDE OROFARYNGEALE INFECTIETHE LEMIERRE SYNDROME: A COMPLICATED OROFARYNGEAL INFECTION
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C. Libeer, J. Bockaert, P. Van Den Brande, W. Geyskens, P. Zachee, and M. Van De Vyvere
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medicine.medical_specialty ,biology ,ved/biology ,business.industry ,education ,ved/biology.organism_classification_rank.species ,General Medicine ,medicine.disease ,biology.organism_classification ,Surgery ,Sepsis ,Angina ,Fusobacterium necrophorum ,cardiovascular system ,medicine ,Lemierre Syndrome ,cardiovascular diseases ,business ,Internal jugular vein ,Bacteroidaceae - Abstract
The Lemierre syndrome or ‘necrobacillosis’ is a post angina sepsis caused by an acute orofaryngeal infection with a secondary thromboflebitis of the internal jugular vein. There are often septic em...
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- 2005
5. P.1.017 GPRIN1, a new 5-HT6 receptor partner involved in its constitutive activity and receptor-induced neuronal differentiation
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C. Pujol, M. Séveno, J. Bockaert, P. Marin, and S. Chaumont-Dubel
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Pharmacology ,Psychiatry and Mental health ,Neurology ,Pharmacology (medical) ,Neurology (clinical) ,Biological Psychiatry - Published
- 2016
6. Idiopathische T-helper lymfocytopenie
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Herman Bobbaers, Greet Hermans, Daniel Engelbert Blockmans, and j Bockaert
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Immunology ,General Medicine - Published
- 1998
7. Combination chemotherapy with vindesine-ifosfamide-cisplatin (VIP) in locally advanced unresectable stage III and in stage IV non-small cell lung cancer: a phase II trial
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F. Verhelst, P. Bertrand, J. Verschuere, S. Marien, L. Roex, Johan Vansteenkiste, A. Verstraete, J. Vandebroek, R. Deman, H. Ulrichts, T. De Beukelaar, Maurits Demedts, J. Bockaert, P. De Muynck, and W. Van Kerckhoven
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Adult ,Male ,Pulmonary and Respiratory Medicine ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Time Factors ,Vindesine ,medicine.medical_treatment ,Adenocarcinoma ,Gastroenterology ,chemistry.chemical_compound ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Weight Loss ,Confidence Intervals ,medicine ,Humans ,Ifosfamide ,Prospective Studies ,Survival rate ,Aged ,Neoplasm Staging ,Chemotherapy ,Chi-Square Distribution ,business.industry ,Induction chemotherapy ,Combination chemotherapy ,Middle Aged ,Nitrogen mustard ,Surgery ,Survival Rate ,Regimen ,Oncology ,chemistry ,Carcinoma, Squamous Cell ,Carcinoma, Large Cell ,Female ,Cisplatin ,business ,medicine.drug - Abstract
The efficacy and toxicity of a regimen adding ifosfamide to the more classical cisplatin-vindesine combination was studied in patients with advanced non-small cell lung cancer. Sixty-four good performance patients with inoperable stage III or stage IV were treated with VIP: vindesine 3 mg/m 2 days 1 and 8, ifosfamide 1200 mg/m 2 and platinum 30 mg/m 2 days 1, 2 and 3, repeated every 4 weeks, up to a maximum of six cycles. Response rate, clinical data and radiological tests were rigourously reviewed by a panel. Overall response rate was 39% (95% confidence interval, 27%–51%) with three patients achieving a complete response; response rate in stage III was 48%. Median survival was 9 months. Toxicity consisted mainly of bone marrow toxicity and nausea/vomiting, but was manageable. There was no renal toxicity greater than grade 2, four severe infections, but no treatment-related deaths. Conclusion: VIP as mentioned above is very active in good performance patients with advanced non-small cell lung cancer. Its activity, together with its manageable toxicity—without severe renal or pulmonary toxicity—makes it an attractive candidate for induction chemotherapy.
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- 1995
8. Epidemiology Of Interstitial Lung Disease (IlD)
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J. Brie, J. Bockaert, M. Roelandt, M. Uydebrouck, Hans Slabbynck, W. Callebaut, Maurits Demedts, M. Ulburghs, L. Simons, K. Vandeurzen, J. Kips, K. De Boeck, J. Van Meerbeeck, and D. Coolen
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medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Interstitial lung disease ,General Medicine ,medicine.disease ,Dermatology ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Lymphangioleiomyomatosis ,Pulmonary fibrosis ,medicine ,Eosinophilic pneumonia ,030212 general & internal medicine ,Sarcoidosis ,business ,education ,Hypersensitivity pneumonitis - Abstract
Worldwide almost no epidemiologic data are available on the prevalence or incidence of interstitial lung diseases (ILD) in the general population. Therefore, a registration programme of ILD-prevalence was organised by the VRGT (Vereniging voor Respiratoire Gezondheidszorg en Tuberculosebestrijding), among about 100 Flemish pneumologists since 1990. Most categories of the classification by Crystal et al. (1) were included and the diagnostic criteria (histology, laboratory tests, clinic, radiology) were registered. The present paper presents the results of 1992-1994: twenty pneumologists had forwarded the summary files of 237 patients to the central office in 1992 (n = 68), 1993 (n = 90) and 1994 (n = 79). The diagnoses that were most frequently made were: sarcoidosis in 27%, idiopathic pulmonary fibrosis in 20%, hypersensitivity pneumonitis in 14% (of which 68% by birds) and collagen-vascular disease in 10% (of which 54% in rheumatoid arthritis). Less frequent causes were eosinophilic pneumonia (4%), inhalation of inorganic material (4%, anthracosilicosis being excluded), histiocytosis X (3%), drugs (3%), angiitis and granulomatosis (2%), pulmonary hemosiderosis (1%), lymphocytic infiltrative lung disease (1%) and lymphangioleiomyomatosis (1%). The order of relative frequencies of the different categories of diseases was the same in the 3 registration years. In 9% of the patients the diagnosis was confined to "undefined fibrosis". The diagnosis was confirmed by histology in 63% of the cases. The overall male-female ratio was nearly one, with, however, a male preponderance in hypersensitivity pneumonitis (22/12), UIP(8/3) and "undefined fibrosis" (14/7).(ABSTRACT TRUNCATED AT 250 WORDS)
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- 1995
9. The PACAP receptor: generation by alternative splicing of functional diversity among G protein-coupled receptors in nerve cells
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Dietmar Spengler, C Pantaloni, Michèle Sebben, Aline Dumuis, Laurent Journot, and J. Bockaert
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Neurons ,Genetics ,Phospholipase C ,Molecular Sequence Data ,Alternative splicing ,Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide ,Adenylate kinase ,Receptors, Cell Surface ,Stimulation ,General Medicine ,Biology ,Cyclase ,Cell biology ,Alternative Splicing ,GTP-Binding Proteins ,Animals ,Humans ,splice ,Amino Acid Sequence ,Receptors, Pituitary Hormone ,Receptor ,hormones, hormone substitutes, and hormone antagonists ,Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I ,G protein-coupled receptor - Abstract
Recent molecular characterization of new G protein-coupled receptors (GPCR) draw attention to alternative splicing as a source of structural diversity. After a brief overview of characterized GPCR splice variants, we will describe in more detail the functional properties of the PACAP type I receptor splice variants. Some of these variants are positively coupled to both adenylate cyclase (AC) and phospholipase C (PLC) whereas others do not elicit any stimulation of the PLC or display a qualitatively intermediate phenotype. The PACAP type I receptor is therefore one of the few examples in which alternative splicing is clearly linked to functional diversity.
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- 1994
10. Chapter 13. Functional Crosstalk between Group I Metabotropic Glutamate Receptors and Ionotropic Glutamate Receptors Controls Synaptic Transmission
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Julie Perroy, Laurent Fagni, and J. Bockaert
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Metabotropic glutamate receptor 8 ,Metabotropic glutamate receptor ,Metabotropic glutamate receptor 5 ,Metabotropic glutamate receptor 4 ,Metabotropic glutamate receptor 7 ,Metabotropic glutamate receptor 1 ,Class C GPCR ,Biology ,Long-term depression ,Neuroscience - Abstract
The glutamatergic synapse harbours both ionotropic and metabotropic receptors that are tightly tethered by intracellular scaffolding proteins. We review how such a multiprotein scaffold supports functional interactions between the two receptor types. We provide evidence from the literature that glutamate metabotropic receptors can either potentiate or inhibit N-methyl-d-aspartate (NMDA) receptors. We also discuss recent data suggesting that these receptor interactions may support important physiological functions such as synaptic plasticity, learning and memory. For instance we describe previous work showing that metabotropic glutamate receptors can induce either long-term potentiation or depression of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor synaptic responses in various regions of the brain and regulate synaptic strength by modulating NMDA receptor facilitation of endocannabinoid release. We report that dysfunctions of these regulations can contribute to mental retardation, drug addiction or neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Together, the data reported in this review highlight the importance of crosstalk between ionotropic and metabotropic glutamate receptors in synaptic functions and related physiological and pathological phenomena.
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- 2011
11. S.01.02 Proteomics and phosphoproteomics for understanding cellular signalling and its disruption in CNS disorders
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Philippe Marin, M.J. Millan, Séverine Chaumont-Dubel, J. Bockaert, and Franck Vandermoere
- Subjects
Pharmacology ,Glutamate receptor ,Neuropathology ,Biology ,medicine.disease ,Olfactory bulb ,Psychiatry and Mental health ,nervous system ,Neurology ,medicine ,biology.protein ,Dementia ,Aging brain ,Locus coeruleus ,Pharmacology (medical) ,Neurology (clinical) ,Reelin ,Cognitive decline ,Neuroscience ,Biological Psychiatry - Abstract
data published by Braak and colleagues. Based on their analysis of postmortem human brains in the age range of 1–100 years, they reported that tau-related neuronal changes appear first in the locus coeruleus, a crucial brain stem nucleus implicated in stress response regulation. The following area to be affected with increasing age is the transentorhinal cortex with its axonal projections from Reelin-expressing cells located in the olfactory bulb. The reduction of Reelin, as a consequence of cumulative environmental injury/disease/infection-induced chronic inflammation [1], accelerates the age-dependent phosphorylation of tau and the instability of interneuronal connections. This will in turn result in a more pronounced synaptic loss and wide-spread formation of neurofibrillary tangles, a correlate of disease progression and dementia severity in patients with AD. Further, reduced Reelinmediated signaling will lead to impairments in NMDAtype of glutamate receptor modulation that might initially affect olfactory information processing, followed by hippocampus-dependent cognitive dysfunctions. In parallel, chronic neuroinflammatory processes presumably provoke axonal stress in long projection neurons, leading to the formation of amyloid plaques and neurofibrillary tangles in cortical association areas, and might, in addition, impair the innate immune system of the brain to adequately support the vulnerable neurons. In addition, ApoE4 potently competes with Reelin for receptor binding and affects its downstream signaling and function. This view positions Reelin and its signaling members in the aging brain as a protective factor against cognitive decline. Accordingly, the reduction in Reelin may shift the balance from healthy to pathological aging. In conclusion, the distinct pathology in the limbicolfactory brain areas and its consistent progression along interconnected neurons as the disease advances has recently received much attention. Here, we highlight the importance of the Reelin-mediated signaling pathway that is maintained in the adult brain and instrumental to modulate synaptic functions and protect neuronal connectivity and integrity. Inflammation/injury-induced dysfunctions of this crucial neurodevelopmental program may indeed underlie the apparent “spread” of the neuropathology across brain networks in patients diagnosed with AD.
- Published
- 2014
12. Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity
- Author
-
Benjamin Chanrion, F. Bertaso, Michael Freissmuth, M. Lerner-Natoli, C. Mannoury la Cour, M.J. Millan, J. Bockaert, and Philippe Marin
- Subjects
Neurotransmitter transporter ,Cell signaling ,Serotonin ,PDZ domain ,Nitric Oxide Synthase Type I ,Nitric Oxide ,Mice ,Animals ,Humans ,Cells, Cultured ,Serotonin transporter ,Serotonin Plasma Membrane Transport Proteins ,Multidisciplinary ,biology ,HEK 293 cells ,Brain ,Transporter ,Biological Sciences ,Cell biology ,Protein Structure, Tertiary ,Biochemistry ,nervous system ,Commentary ,biology.protein ,Calcium ,Signal Transduction - Abstract
The spatiotemporal regulation of neurotransmitter transporters involves proteins that interact with their intracellular domains. Using a proteomic approach, we identified several proteins that interact with the C terminus of the serotonin transporter (SERT). These included neuronal nitric oxide synthase (nNOS), a PSD-95/Disc large/ZO-1 (PDZ) domain-containing protein recruited by the atypical PDZ binding motif of SERT. Coexpression of nNOS with SERT in HEK293 cells decreased SERT cell surface localization and 5-hydroxytryptamine (5-HT) uptake. These effects were absent in cells transfected with SERT mutated in its PDZ motif to prevent physical association with nNOS, and 5-HT uptake was unaffected by activation or inhibition of nNOS enzymatic activity. 5-HT uptake into brain synaptosomes was increased in both nNOS-deficient and wild-type mice i.v. injected with a membrane-permeant peptidyl mimetic of SERT C terminus, which disrupted interaction between SERT and nNOS, suggesting that nNOS reduces SERT activity in vivo . Furthermore, treating cultured mesencephalic neurons with the mimetic peptide similarly increased 5-HT uptake. Reciprocally, indicating that 5-HT uptake stimulates nNOS activity, NO production was enhanced on exposure of cells cotransfected with nNOS and SERT to 5-HT. This effect was abolished by 5-HT uptake inhibitors and absent in cells expressing SERT mutated in its PDZ motif. In conclusion, physical association between nNOS and SERT provides a molecular substrate for their reciprocal functional modulation. In addition to showing that nNOS controls cell surface localization of SERT, these findings provide evidence for regulation of cellular signaling (NO production) by a substrate-carrying transporter.
- Published
- 2007
13. S.24.04 Cognitive deficits of schizophrenia and their control by the mTOR pathway
- Author
-
Julie Meffre, M.J. Millan, Philippe Marin, C. Mannoury la Cour, David J. G. Watson, Kevin C. F. Fone, and J. Bockaert
- Subjects
Pharmacology ,business.industry ,Schizophrenia (object-oriented programming) ,Cognition ,Psychiatry and Mental health ,Neurology ,Medicine ,Pharmacology (medical) ,Neurology (clinical) ,business ,Control (linguistics) ,Neuroscience ,Biological Psychiatry ,PI3K/AKT/mTOR pathway - Published
- 2015
14. Récepteurs couplés aux protéines G et leurs ligands
- Author
-
J. Bockaert
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,General Medicine - Abstract
Parmi les familles de proteines des genomes d’invertebres et de vertebres, les recepteurs couples aux proteines G (RCPGs) sont sans aucun doute les plus versatiles. Leur adaptation a permis la generation d’un grand nombre de recepteurs responsables de la reconnaissance et de l’action de ligands aussi divers que la lumiere, des odeurs, des pheromones, des molecules gustatives, des nucleotides, des nucleosides, des acides amines et leurs derives, des acides gras et des lipides, des acides biliaires, des peptides, des proteines et beaucoup d’autres restant a decouvrir. Chez l’homme, (3 % des genes), les recepteurs aux odeurs representent 500 entites et les « endo-RCPGs »(recepteurs ayant un ligand endogene, hormone, neurotransmetteurs, acide gras, …) 360 entites dont 130 recepteurs orphelins. Les RCPGs sont la cible de plus de 30 % des medicaments. Les RCPG ont ete classes en cinq familles : la famille A, la plus nombreuse, contient la rhodopsine. La famille B est celle de grands peptides, tels la calcitonine, la secretine… et des recepteurs d’adhesion. La classe C est constituee par les recepteurs du glutamate, du GABA, et des substances sucrees, du Ca2+ et certaines pheromones. La classe C possede un large domaine extracellulaire organise en deux lobes qui se referment sur les agonistes declenchant l’activation, mais restent en position ouverte par fixation des antagonistes. La famille D contient les recepteurs Frizzled et Smoothened. Depuis moins de 10 ans, de nombreux GPCRs ont ete cristallises fournissant de donnees importantes de leur structure et de leur activation.
- Published
- 2015
15. [The Lemierre syndrome: a complicated oropharyngeal infection]
- Author
-
C, Libeer, J, Bockaert, P, Van den Brande, P, Zachee, M, Van de Vyvere, and W, Geyskens
- Subjects
Adult ,Male ,Fusobacterium necrophorum ,Sepsis ,Fusobacterium Infections ,Humans ,Female ,Pharyngitis ,Thrombosis ,Syndrome ,Jugular Veins ,Tomography, X-Ray Computed - Abstract
The Lemierre syndrome or 'necrobacillosis' is a post angina sepsis caused by an acute oropharyngeal infection with a secondary thrombophlebitis of the internal jugular vein. There are often septic emboli in the lungs, although intestinal organs can also be affected. This syndrome is caused by the strictly anaerobic gram-negative pathogen Fusobacterium necrophorum, sometimes in combination with other pathogens. The patient typically presents with high fever, pain in the neck, malaise and dyspnoea one week after the start of an angina. Plain chest radiograph shows bilateral nodular infiltrates, ultrasound reveals a thrombophlebitis of the internal jugular vein. CT scan can be useful to confirm the diagnosis and possible complications. In the beginning there is often a transient hyperbilirubinemia with toxic inflammatory blood results. Under the correct antibiotic regime complete recovery can be obtained.
- Published
- 2005
16. P.1.007 A proteomic and functional analysis reveals that 5-HT6 receptors modulate neuronal differentiation by recruitment of Cdk5
- Author
-
C. Mannoury la Cour, F. Duhr, Philippe Marin, J. Bockaert, M.J. Millan, Delphine S. Dupuis, Martial Séveno, and Séverine Chaumont-Dubel
- Subjects
Pharmacology ,Psychiatry and Mental health ,Neurology ,Functional analysis ,Cyclin-dependent kinase 5 ,Neuronal differentiation ,Pharmacology (medical) ,Neurology (clinical) ,Biology ,Receptor ,Biological Psychiatry ,Cell biology - Published
- 2013
17. Impaired somatodendritic responses to pituitary adenylate cyclase-activating polypeptide (PACAP) of supraoptic neurones in PACAP type I -receptor deficient mice
- Author
-
F, Jamen, G, Alonso, I, Shibuya, H, Widmer, C-M, Vacher, A, Calas, J, Bockaert, P, Brabet, and G, Dayanithi
- Subjects
Male ,Mice, Knockout ,Nerve Endings ,Neurons ,Vasopressins ,Neuropeptides ,Osmolar Concentration ,Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide ,Dendrites ,Intracellular Membranes ,Oxytocin ,Rats ,Mice ,Pituitary Gland, Posterior ,Animals ,Pituitary Adenylate Cyclase-Activating Polypeptide ,Protein Isoforms ,Calcium ,Calcium Signaling ,Receptors, Pituitary Hormone ,Rats, Wistar ,Supraoptic Nucleus ,Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - Abstract
The role of pituitary adenylate cyclase-activating polypeptide (PACAP) type I receptor (PAC1 receptor) in regulating hypothalamic supraoptic neurones was investigated using PAC1 receptor-deficient male mice (PAC1-/-). The effects of PACAP on [Ca2+]i were investigated in freshly dissociated supraoptic neurones and on the somatodendritic release of vasopressin and oxytocin, examined on intact supraoptic nuclei. In supraoptic neurones from wild-type mice (PAC1+/+), 100 nm PACAP induced an increase in [Ca2+]i and release of vasopressin and oxytocin, whereas in heterozygous (PAC1+/-) and null-mutant mice (PAC1-/-), PACAP was much less effective. PACAP had no effect on these two parameters when applied to isolated neurohypophysial nerve terminals of PAC1+/+ and PAC1-/- mice, and rats. In conclusion, the PAC1 receptor is solely responsible for the PACAP-induced [Ca2+]i signalling and secretion of vasopressin and oxytocin in the somatodendritic region of supraoptic neurones.
- Published
- 2003
18. P.1.008 Recruitment of the mTOR complex 1 by 5-HT6 receptors: potential role in the cognitive deficits of schizophrenia
- Author
-
Kevin C. F. Fone, David M. Watson, Philippe Marin, Julie Meffre, J. Bockaert, C. Mannoury la Cour, M.J. Millan, and Florence Loiseau
- Subjects
Pharmacology ,Cued speech ,medicine.drug_class ,Social anxiety ,Cognition ,social sciences ,Extinction (psychology) ,medicine.disease ,Anxiolytic ,humanities ,Psychiatry and Mental health ,Neurology ,Schizophrenia ,medicine ,Autism ,Pharmacology (medical) ,Neurology (clinical) ,Fear conditioning ,Psychology ,Neuroscience ,Biological Psychiatry - Abstract
Oxytocin (OT) has received substantial interest in recent years due to its pro-social and anxiolytic properties. In this study we investigated whether central OT administration facilitates the extinction of social and cued fear in rodents. Social fear was induced by social fear conditioning [1], while cued fear was induced by cued fear conditioning [2]. Social and cued fear extinction were performed 24 h later in a novel environment. OT was administered intracerebroventricularly 10min before the extinction procedure. While central OT completely blocked social fear expression, reversing thereby social fear, it impaired cued fear extinction. Both the facilitatory effect on social fear extinction and the impairing effect on cued fear extinction were mediated by the OT receptors, as administration of an OT receptor antagonist prior to OT blocked the observed effects. At the doses used in the fear extinction studies OT did not alter home cage locomotion, indicating that the observed effects were not a result of impaired locomotion. Taken together, this data suggests that OT has a differential effect on fear extinction in social versus nonsocial contexts, and draws attention to the implications of using OT as a potential adjunct drug in combination with behavioral therapy for psychiatric disorders. Therefore, OT might represent a therapeutically-promising approach in patients with deficits in social functioning, such as social anxiety disorder and autism spectrum disorders. However, in patients where the fear does not involve a social component, such as post-traumatic stress disorder, OT may delay fear extinction.
- Published
- 2012
19. AMPA receptor activation induces association of G-beta protein with the alpha subunit of the sodium channel in neurons
- Author
-
P, Marin, L, Fagni, Y, Torrens, G, Alcaraz, F, Couraud, J, Bockaert, J, Glowinski, and J, Prémont
- Subjects
Central Nervous System ,Neurons ,Nerve Tissue Proteins ,Neural Inhibition ,Tetrodotoxin ,Heterotrimeric GTP-Binding Proteins ,Immunohistochemistry ,Synaptic Transmission ,Sodium Channels ,Sodium-Calcium Exchanger ,Membrane Potentials ,Mitochondria ,NAV1.1 Voltage-Gated Sodium Channel ,Mice ,Fetus ,Pregnancy ,Excitatory Amino Acid Agonists ,Animals ,Calcium ,Female ,Calcium Signaling ,Receptors, AMPA ,Excitatory Amino Acid Antagonists ,Cells, Cultured - Abstract
Glutamatergic transmission is mediated by ionotropic receptors that directly gate cationic channels and metabotropic receptors that are coupled to second messenger generating systems and to ionic channels via heterotrimeric guanine-nucleotide binding- (G) proteins. This distinction cannot be made for the ionotropic receptor subclass activated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), which has been shown to be physically associated with the alpha-subunit of Gi1 protein and activates this G-protein. Here, we report that, in addition to a Ca2+ influx, AMPA induces the mobilization of Ca2+ from the mitochondrial pool by reversing the mitochondrial Na+/Ca2+ exchanger in mouse neurons in primary culture. Both processes required the activation of tetrodotoxin-sensitive Na+ channels. AMPA receptor activation modified the gating properties of the Na+ channel, independently of the AMPA current, suggesting a G-protein-mediated process. Indeed, co-immunoprecipitation experiments indicated that AMPA receptor activation induced the association of Gbeta with the alpha-subunit of the Na+ channel. These results suggest that, in addition to its ionic channel function, the AMPA receptor is coupled to Na+ channels through G-proteins and that this novel metabotropic function is involved in the control of neuronal excitability.
- Published
- 2002
20. Metabotropic glutamate receptors (mGluRs)
- Author
-
J. P. Pin, J. Bockaert, and L. Fagni
- Subjects
Metabotropic glutamate receptor 8 ,Metabotropic glutamate receptor 5 ,Chemistry ,Metabotropic glutamate receptor 4 ,Metabotropic glutamate receptor 7 ,Metabotropic glutamate receptor 6 ,Metabotropic glutamate receptor 1 ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,Pharmacology - Published
- 2001
21. S.07.01 A proteomic and functional analysis reveals that 5-HT6 receptors modulate neuronal differentiation by recruitment of Cdk5
- Author
-
F. Duhr, M. Séveno, C. Marmoury la Cour, D. Dupuis, M.J. Millan, J. Bockaert, P. Marin, and S. Chaumont-Dubel
- Subjects
Pharmacology ,Psychiatry and Mental health ,Neurology ,Pharmacology (medical) ,Neurology (clinical) ,Biological Psychiatry - Published
- 2013
22. Chapter II Brain PACAP/VIP receptors: regional distribution, functional properties and physiological relevance
- Author
-
J. Bockaert, Laurent Journot, P.J. Magistretti, and J.-L. Martin
- Subjects
chemistry.chemical_classification ,endocrine system ,Vasoactive intestinal peptide ,Central nervous system ,Peptide ,Ligand (biochemistry) ,VIP Receptors ,medicine.anatomical_structure ,chemistry ,Biochemistry ,medicine ,Distribution (pharmacology) ,Binding site ,Receptor ,hormones, hormone substitutes, and hormone antagonists - Abstract
Publisher Summary Vasoactive Intestinal Peptide (VIP) is a 28-amino acid basic peptide, amidated at the carboxyl Terminus. VIP was first isolated from porcine intestine as a peptide potently inducing vasodilatation in the canine femoral artery. Early studies recognized that VIP acts through interaction with a specific high-affinity binding site. However, it was also realized that some of the effects of VIP required concentrations of the peptide in the micromolar range, suggesting the existence of at least an additional receptor whose ligand was suggested to share some structural homology with VIE The discovery of PACAP-38 and PACAP-27 fulfilled these expectations since, as mentioned earlier, PACAP-27 displays 68% identity with VIP and nanomolar concentrations of both forms of PACAP reproduce the effect of micromolar concentrations of VIP More surprisingly, PACAP-27 and-38 were also found to bind with high affinity to VIP binding sites. This chapter provides an overview of the regional distribution of VIP and PACAP binding sites in rodents and address more recent aspects related to the molecular characterization of VIP and PACAP receptors in the central nervous system. In addition we have put a particular emphasis on the most salient functional properties of VIP/PACAP receptors and on the physiological actions that result from their activation.
- Published
- 2000
23. mGluR7-like metabotropic glutamate receptors inhibit NMDA-mediated excitotoxicity in cultured mouse cerebellar granule neurons
- Author
-
M, Lafon-Cazal, L, Fagni, M J, Guiraud, S, Mary, M, Lerner-Natoli, J P, Pin, R, Shigemoto, and J, Bockaert
- Subjects
Neurons ,Kainic Acid ,N-Methylaspartate ,Patch-Clamp Techniques ,Cell Death ,Neurotoxins ,Glutamic Acid ,Receptors, Metabotropic Glutamate ,Receptors, N-Methyl-D-Aspartate ,Mice ,Phosphoserine ,Neuroprotective Agents ,Cerebellum ,Excitatory Amino Acid Agonists ,Animals ,Cycloleucine ,Calcium Channels ,Receptors, AMPA ,Dizocilpine Maleate ,Propionates ,Cyclic GMP ,Excitatory Amino Acid Antagonists ,Microtubule-Associated Proteins ,Cells, Cultured - Abstract
Glutamate-induced glutamate release may be involved in the delayed neuronal death induced by N-methyl-D-aspartate (NMDA). In order to examine a possible modulatory effect of the presynaptic group III mGluRs on glutamate excitotoxicity, the effect of L-2-amino-4-phosphonobutyrate (L-AP4) was examined on NMDA-induced delayed death of mouse cerebellar granule neurons in culture. We found that L-AP4, at high concentration (in the millimolar range), inhibited in a non-competitive manner the NMDA-induced toxicity. This effect was mimicked by high concentration of L-serine-o-phosphate (L-SOP), and was inhibited by pertussis toxin (PTX) indicating the involvement of a Gi/o protein. This suggests the involvement of mGluR7 in the L-AP4 effect, and this was consistent with the detection of both mGluR7 protein and mRNA in these cultured neurons. To examine the mechanism of the L-AP4-induced protection from excitotoxic damage, the effect of L-AP4 on glutamate release was examined. L-AP4 (or = 1 mM) noncompetitively inhibited by more than 60% the glutamate release induced by NMDA during the insult. We also observed that the 10-min NMDA receptor stimulation resulted in a dramatic increase in the extracellular glutamate concentration reaching 6000% of the control value 24 h after the insult. This large increase was also inhibited when NMDA was applied in the presence ofor = 1 mM L-AP4. Part of the L-AP4-induced protection from excitotoxic damage of granule neurons may therefore result from the inhibition of the vicious cycle: dying cells release glutamate, glutamate induced cell death. The present results add to the hypothesis that presynaptic mGluRs, probably mGluR7, may be the targets of drugs decreasing glutamate release and then neuronal death observed in some pathological situations.
- Published
- 1999
24. The neuronal death induced by endotoxic shock but not that induced by excitatory amino acids requires TNF-alpha
- Author
-
F, de Bock, B, Derijard, J, Dornand, J, Bockaert, and G, Rondouin
- Subjects
Lipopolysaccharides ,Neurons ,Kainic Acid ,N-Methylaspartate ,Cell Death ,Free Radicals ,Tumor Necrosis Factor-alpha ,Excitatory Amino Acids ,Nitric Oxide ,Hippocampus ,Shock, Septic ,p38 Mitogen-Activated Protein Kinases ,Rats ,Enzyme Activation ,Interferon-gamma ,Organ Culture Techniques ,Receptors, Glutamate ,Calcium-Calmodulin-Dependent Protein Kinases ,Animals ,Microglia ,Mitogen-Activated Protein Kinases ,Reactive Oxygen Species - Abstract
We studied, using organotypic hippocampal slices in culture, the role of pro-inflammatory cytokines, oxygen radicals and nitric oxide in neuronal death induced either by endotoxic insult [interferon (IFN) gamma, 24 h followed by lipopolysaccharide, 24 h] or by glutamate receptor-mediated excitotoxic insult. We demonstrated that neuronal death induced by endotoxic insult was absolutely dependent on the synthesis of tumour necrosis factor alpha (TNF-alpha). Indeed, TNF-alpha antibodies and SB203580, an inhibitor of p38 stress kinase known to block TNF-alpha and other cytokine synthesis, completely protected neurons from the endotoxic insult. Inhibiting oxygen radical and nitric oxide productions also reduced the endotoxic shock. We also showed that after priming the cultures with IFN-gamma, TNF-alpha was unable to induce neuronal death unless oxygen-free radicals were exogenously provided. In contrast, although glutamate receptor-induced excitotoxicity was associated with a low TNF-alpha synthesis and a modest activation of p38 stress kinase, neither TNF-alpha antibodies nor SB203580 were able to decrease excitotoxic neuronal insult. We did not reduce glutamate receptor-induced neuronal death with superoxide dismutase plus catalase. In conclusion, although inflammation follows glutamate receptor-mediated neurotoxicity, the mechanisms by which an endotoxic insult triggers neuronal death are different from those involved in excitotoxicity.
- Published
- 1998
25. [Use of a G-protein-coupled receptor to communicate. An evolutionary success]
- Author
-
J, Bockaert and J P, Pin
- Subjects
Evolution, Molecular ,Models, Molecular ,Structure-Activity Relationship ,GTP-Binding Proteins ,Catalytic Domain ,Molecular Sequence Data ,Receptors, Cell Surface ,Protein Structure, Tertiary ,Signal Transduction - Abstract
Among membrane-bound receptors, the seven transmembrane receptors are the most abundant (several thousand, 1% of the genome). They were the most successful during evolution. They are capable of transducing messages as different as photons, organic odorants, nucleotides, nucleosides, peptides, lipids, proteins, etc. They are catalysts of the GDP/GTP nucleotide exchange on heterotrimeric G proteins. They are therefore also called 'G-protein-coupled receptors' (GPCR). G proteins are composed of three subunits, G alpha and two undissociable subunits, G beta gamma. There are at least three families of GPCR showing no sequence similarity. Among G proteins, some have been crystallized (including under the heterotrimeric form) and their structure as well as their activation mechanisms are well known. The structures of GPCR are less known owing to the difficulty in crystallizing membrane-bound proteins. Indirect studies (mutations, 2D crystallization of rhodopsine, molecular modelling, etc.) lead to a useful model of the 'central core' composed of the seven transmembrane domains and of its structural modifications during activation. The intimate contact zones between GPCR and G proteins include, on the GPCR side, domains of intracellular loops and C-terminal, which are specific for each family and on the G protein side, essentially the N- et C-terminal domains plus the alpha 4-beta 6 loop. GPCR can adopt several 'active' conformations some of them being found in mutated receptors responsible for pathologies.
- Published
- 1998
26. hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer
- Author
-
F. Apiou, Ary A. Hoffmann, Benoit Bilanges, Laurent Journot, Elisabetta Ciani, J. Bockaert, Annie Varrault, C Pantaloni, and Dietmar Spengler
- Subjects
Transcriptional Activation ,Tumor suppressor gene ,Cell ,Molecular Sequence Data ,Apoptosis ,Cell Cycle Proteins ,Biology ,DNA-binding protein ,Loss of heterozygosity ,Transactivation ,Mice ,Neoplasms ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Genes, Tumor Suppressor ,Amino Acid Sequence ,Transcription factor ,Zinc finger ,Multidisciplinary ,Sequence Homology, Amino Acid ,Tumor Suppressor Proteins ,Chromosome Mapping ,Zinc Fingers ,Biological Sciences ,Molecular biology ,DNA-Binding Proteins ,Blotting, Southern ,medicine.anatomical_structure ,Chromosomal region ,Cancer research ,Trans-Activators ,Chromosomes, Human, Pair 6 ,Transcription Factors - Abstract
We previously reported the identification of mZac, a novel mouse zinc finger protein that shared with p53 the ability to regulate concomitantly apoptosis and cell cycle progression. We describe here the isolation, chromosomal localization, and functional in vitro characterization of its human homolog. hZAC is a widely expressed zinc finger protein that reveals transactivation and DNA-binding activity. hZAC inhibits tumor cell growth through induction of apoptotic cell death and G 1 arrest. Thus hZAC, like its mouse counterpart, displays antiproliferative properties through pathways known to be central to the activity of p53. We mapped hZAC on chromosome 6q24-q25, a region frequently deleted in many solid tumors. Indeed, allelic loss at 6q24-q25 has been shown in breast and ovary cancers, melanomas, astrocytomas, and renal cell carcinomas. Furthermore, Abdollahi et al. [Abdollahi, A., Godwin, A. K., Miller, P. D., Getts, L. A., Schultz, D. C., Tagushi, T., Testa, J. R. & Hamilton, T. C. (1997) Cancer Res. 57, 2029–2034] recently isolated ZAC through its loss of expression in a surface epithelial ovary tumor model and accordingly named it Lot for “lost on transformation.” In view of these observations, the functional properties we report here provide further arguments to consider hZAC as a tumor suppressor gene candidate.
- Published
- 1998
27. Localization of 5-HT4 Receptors in Vertebrate Brain and Their Potential Behavioral Roles
- Author
-
J. Bockaert and Aline Dumuis
- Subjects
Cloning ,Kainic acid ,Anatomy ,Biology ,musculoskeletal system ,Cell biology ,Adenylyl cyclase ,chemistry.chemical_compound ,Globus pallidus ,chemistry ,Receptor ,Peptide sequence ,Transduction (physiology) ,5-HT receptor - Abstract
In 1988, we found in mouse colliculi neurons grown in primary cultures, a 5-HT receptor which stimulated cAMP production and had a pharmacology different from that of the receptors described at that time, i.e., the 5-HT1, 5-HT2, and 5-HT3 receptors. In particular, highly potent and specific 5-HT1,2,3 antagonists were unable to block this receptor. We therefore proposed to name it, without any permission, the 5-HT4 receptor.1 Fortunately, based on their pharmacology, transduction mechanisms, physiology and finally, cloning, it became rapidly evident that this proposition was correct. The 5-HT4 receptor is the only member of its class because it shows little amino acid sequence relationship to all other serotonin receptors, including those positively coupled to the adenylyl cyclase (AC) (the 5-HT6 and 5-HT7 receptors).2–6
- Published
- 1998
28. S.04.02 Recruitment of the mTOR complex 1 by 5-HT6 receptors: potential role in the cognitive deficits of schizophrenia
- Author
-
J. Meffre, C. Mannoury la Cour, D. Watson, F. Loiseau, K. Fone, M.J. Millan, J. Bockaert, and P. Marin
- Subjects
Pharmacology ,Psychiatry and Mental health ,Neurology ,Pharmacology (medical) ,Neurology (clinical) ,Biological Psychiatry - Published
- 2012
29. Glutamate stimulates insulin secretion and improves glucose tolerance in rats
- Author
-
Raymond Puech, Marie-Madeleine Loubatières-Mariani, G. Bertrand, and J. Bockaert
- Subjects
Male ,medicine.medical_specialty ,Consciousness ,Physiology ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Administration, Oral ,Glutamic Acid ,Biology ,chemistry.chemical_compound ,Eating ,In vivo ,Physiology (medical) ,Internal medicine ,Glucose Intolerance ,Insulin Secretion ,medicine ,Animals ,Insulin ,Anesthesia ,Rats, Wistar ,Receptor ,Neurotransmitter ,Pancreatic hormone ,Glutamate receptor ,Antagonist ,Glutamic acid ,Fasting ,Rats ,Endocrinology ,chemistry ,Injections, Intravenous - Abstract
We previously showed in vitro that glutamate stimulates insulin release via an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Here we address a more physiological question concerning the in vivo effect of intravenously or orally administered glutamate on insulinemia and glycemia in fed and fasted rats. In anesthetized fed rats, the intravenous administration of glutamate at 9 and 30 mg/kg transiently increased insulinemia in a dose-dependent manner. The insulin-secretory effect of glutamate (9 mg/kg) was blocked by an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. In anesthetized fasted rats, glutamate at 9 mg/kg was ineffective, but during an intravenous glucose tolerance test (0.5 g/kg), glutamate markedly potentiated insulin release and increased the glucose disappearance rate. In conscious rats, the intragastric administration of glutamate at 200 mg/kg elicited a transient insulin response in fed animals and had no effect in fasted animals but, during an oral glucose tolerance test (1 g/kg), enhanced insulin secretion and reduced the hyperglycemia. Glutamate was effective at plasma concentrations of 200-300 microM. In conclusion, intravenously and orally administered glutamate stimulates insulin secretion in vivo via an excitatory amino acid receptor and improves glucose tolerance.
- Published
- 1995
30. Involvement of divalent ions in the nitric oxide-induced blockade of N-methyl-D-aspartate receptors in cerebellar granule cells
- Author
-
L, Fagni, M, Olivier, M, Lafon-Cazal, and J, Bockaert
- Subjects
Neurons ,N-Methylaspartate ,Cations, Divalent ,Glycine ,Hydrogen-Ion Concentration ,Nitric Oxide ,Receptors, N-Methyl-D-Aspartate ,Membrane Potentials ,Mice ,Cerebellum ,Molsidomine ,Animals ,Oxidation-Reduction ,Cells, Cultured - Abstract
We have previously shown that nitric oxide blocks the N-methyl-D-aspartate (NMDA) receptor without affecting the agonist binding site. We now report that in cerebellar granule cells nitric oxide decreases the NMDA channel conductance and open probability, in voltage-dependent and -independent manners, respectively, by acting on an extracellular site different from the redox, glycine, and pH modulatory sites of the receptor-channel complex. This inhibition is not additive with those of Mg2+ and Zn2+. Moreover, removal of trace concentrations of metal ions in the external medium by means of metal ion-chelators significantly reduced the inhibitory action of nitric oxide on NMDA currents. These results indicate that divalent ions are required for the blockade of NMDA receptors by NO donors.
- Published
- 1995
31. Differential expression of pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide receptor subtypes in clonal pituitary somatotrophs and gonadotrophs
- Author
-
J Bockaert, I Piuz, Werner Schlegel, S R Rawlings, and Laurent Journot
- Subjects
endocrine system ,Pituitary gland ,medicine.medical_specialty ,Cell type ,Somatotropic cell ,Vasoactive intestinal peptide ,Molecular Sequence Data ,Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide ,Gene Expression ,Biology ,Gonadotropic cell ,Phosphatidylinositols ,Polymerase Chain Reaction ,Cell Line ,Endocrinology ,Anterior pituitary ,Nickel ,Pituitary Gland, Anterior ,Internal medicine ,medicine ,Cyclic AMP ,Tumor Cells, Cultured ,Animals ,Receptors, Pituitary Hormone ,Receptor ,DNA Primers ,Neurotransmitter Agents ,Base Sequence ,Dose-Response Relationship, Drug ,Neuropeptides ,Clone Cells ,Rats ,Kinetics ,medicine.anatomical_structure ,Liver ,Cell culture ,Pituitary Adenylate Cyclase-Activating Polypeptide ,Receptors, Vasoactive Intestinal Peptide ,Calcium ,hormones, hormone substitutes, and hormone antagonists ,Vasoactive Intestinal Peptide - Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are hypothalamic factors believed to play a role in the regulation of anterior pituitary cell function. However, little is known about the expression of PACAP/VIP receptor (PVR) subtypes in such cells. Three PVR subtypes have recently been cloned: the PACAP-selective PVR1, and PVR2 and PVR3, which exhibit similar affinities for PACAP and VIP. In the present study we used the reverse transcription-polymerase chain reaction with PVR-specific primers to identify the PVR messenger RNAs (mRNAs) expressed in the somatotroph-like GH4C1 and the gonadotroph-like alpha T3-1 cell lines. In parallel, the effects of PACAP and VIP on intracellular signaling were studied. GH4C1 cells were found to express mRNA only for the PVR3, and neither PVR1 nor PVR2 mRNA was found. PACAP and VIP stimulated Ca2+ influx responses in individual GH4C1 cells and were equipotent in stimulating cAMP production (EC50, 15 nM) in GH4C1 cell populations, but failed to stimulate inositol phospholipid (PI) turnover, results consistent with the expression of a PVR3. In contrast, alpha T3-1 cells expressed mRNA for PVR1 and PVR3, but not PVR2. The predominant splice variant forms of PVR1 observed were PVR1s and PVR1hop, although the other forms (PVR1hiphop and PVR1hip) were also seen at much lower levels. PACAP stimulated a Ca2+ store-dependent Ca2+ spike and a sustained Ca2+ influx in individual alpha T3-1 cells, whereas VIP only stimulated Ca2+ influx. PACAP (EC50, 3 nM) was approximately 1000-fold more potent than VIP (EC50, approximately 3 microM) in stimulating cAMP production. PACAP also stimulated PI turnover (EC50, approximately 20 nM), whereas VIP stimulated PI turnover only at very high (10 microM) concentrations. These results are indicative of the expression of a PVR1. Rat anterior pituitary tissue expressed mRNAs for PVR1, PVR3, and low levels of PVR2. The coexpression of different PVRs in the same cell type and the differential expression of PVRs in different cell types would allow for a complex regulation of anterior pituitary gland function by PACAP and VIP.
- Published
- 1995
32. [The role of nitric oxide and superoxides in the neurotoxicity of glutamate]
- Author
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L, Fagni, M, Lafon-Cazal, M, Lerner-Natoli, G, Rondouin, and J, Bockaert
- Subjects
Mice ,Superoxides ,Animals ,Glutamic Acid ,Nervous System Diseases ,Nitric Oxide ,Cells, Cultured ,Rats - Abstract
Glutamate is the major neurotransmitter of the mammalian brain. Stimulation of glutamate receptors, especially the subgroup of NMDA receptors, induces nitric oxide and arachidonic acid synthesis in neurons. These agents freely diffuse across membranes and thus can play roles of messengers in particular brain functions. The aim of our study was to identify these roles in in vitro and in vivo models from mouse and rat. Exaggerated stimulation of NMDA receptors leads to neurological disorders such as some types of epilepsy and neurodegenerative diseases. We show that superoxide ions, which probably result from metabolic degradation of arachidonic acid, would be responsible of the neurotoxic action of NMDA. On the other hand, we observed that nitric oxide inhibits NMDA receptors. This effect would protect animals against epileptic and neurodegenerative diseases mediated by over-stimulation of these receptors. This endogenous regulation may play important roles in the functioning of glutamatergic neurotransmission.
- Published
- 1995
33. Homologous desensitization of 5-hydroxytryptamine4 receptors in rat esophagus: functional and second messenger studies
- Author
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P, Rondé, H, Ansanay, A, Dumuis, R, Miller, and J, Bockaert
- Subjects
Serotonin ,Sulfonamides ,Indoles ,Time Factors ,Muscle Relaxation ,Muscle, Smooth ,In Vitro Techniques ,Bridged Bicyclo Compounds, Heterocyclic ,Rats ,Bridged Bicyclo Compounds ,Esophagus ,Receptors, Serotonin ,Benzamides ,Cyclic AMP ,para-Aminobenzoates ,Animals ,4-Aminobenzoic Acid ,Signal Transduction - Abstract
We have studied agonist-induced desensitization of 5-hydroxytryptamine (5-HT4) receptor-mediated relaxation and 5-HT4 receptor-mediated increases in cAMP in rat esophageal tunica muscularis mucosae. In both cases, the desensitization time course was biphasic. The first phase was very rapid because more than 50% of desensitization was obtained after a 5-min incubation period with 10 microM of 5-HT. The second phase was slower and led to a complete suppression of the response after 2 h. Desensitization progressively reduced the maximal relaxation of esophagus induced by 5-HT without significantly affecting the EC50. Desensitization was a receptor-mediated event because cross-desensitization was observed between two chemically unrelated 5-HT4 receptor agonists, 5-HT itself and (S)-zacopride. Inasmuch as the kinetics of desensitization were the same when second messenger production or final responses were measured, this suggests that the limiting step in the desensitization process is at the level of the receptor itself or in its coupling to adenylyl cyclase. The desensitization was of the homologous type because exogenously applied cAMP, 8-Bromo-cAMP, or compounds increasing cAMP in the esophageal tunica muscularis mucosae such as isoproterenol and forskolin, were unable to induce any desensitization of the 5-HT4 receptor-induced relaxation response. Homologous desensitization was not followed by a rapid down-regulation of 5-HT4 receptors because no decrease in the Bmax of [3H]-GR113808 binding was observed after 30-min incubation with 10 microM 5-HT.
- Published
- 1995
34. Epidemiology of interstitial lung disease (ILD) in flanders: registration by pneumologists in 1992-1994. Working group on ILD, VRGT. Vereniging voor Respiratoire Gezondheidszorg en Tuberculosebestrijding
- Author
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M, Roelandt, M, Demedts, W, Callebaut, D, Coolen, H, Slabbynck, J, Bockaert, J, Kips, J, Brie, M, Ulburghs, and K, De Boeck
- Subjects
Adult ,Male ,Belgium ,Sarcoidosis ,Pulmonary Fibrosis ,Prevalence ,Humans ,Female ,Registries ,Middle Aged ,Lung Diseases, Interstitial ,Aged ,Alveolitis, Extrinsic Allergic - Abstract
Worldwide almost no epidemiologic data are available on the prevalence or incidence of interstitial lung diseases (ILD) in the general population. Therefore, a registration programme of ILD-prevalence was organised by the VRGT (Vereniging voor Respiratoire Gezondheidszorg en Tuberculosebestrijding), among about 100 Flemish pneumologists since 1990. Most categories of the classification by Crystal et al. (1) were included and the diagnostic criteria (histology, laboratory tests, clinic, radiology) were registered. The present paper presents the results of 1992-1994: twenty pneumologists had forwarded the summary files of 237 patients to the central office in 1992 (n = 68), 1993 (n = 90) and 1994 (n = 79). The diagnoses that were most frequently made were: sarcoidosis in 27%, idiopathic pulmonary fibrosis in 20%, hypersensitivity pneumonitis in 14% (of which 68% by birds) and collagen-vascular disease in 10% (of which 54% in rheumatoid arthritis). Less frequent causes were eosinophilic pneumonia (4%), inhalation of inorganic material (4%, anthracosilicosis being excluded), histiocytosis X (3%), drugs (3%), angiitis and granulomatosis (2%), pulmonary hemosiderosis (1%), lymphocytic infiltrative lung disease (1%) and lymphangioleiomyomatosis (1%). The order of relative frequencies of the different categories of diseases was the same in the 3 registration years. In 9% of the patients the diagnosis was confined to "undefined fibrosis". The diagnosis was confirmed by histology in 63% of the cases. The overall male-female ratio was nearly one, with, however, a male preponderance in hypersensitivity pneumonitis (22/12), UIP(8/3) and "undefined fibrosis" (14/7).(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
35. 5-Hydroxytryptamine1A receptor synthetic peptides. Mechanisms of adenylyl cyclase inhibition
- Author
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A, Varrault, D, Le Nguyen, S, McClue, B, Harris, P, Jouin, and J, Bockaert
- Subjects
Male ,Molecular Sequence Data ,Moths ,Hippocampus ,Protein Structure, Secondary ,Cell Line ,Mice ,GTP-Binding Proteins ,Animals ,Humans ,Amino Acid Sequence ,Virulence Factors, Bordetella ,Rats, Wistar ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Cell Membrane ,Colforsin ,3T3 Cells ,Peptide Fragments ,Clone Cells ,Rats ,Kinetics ,Pertussis Toxin ,Guanosine 5'-O-(3-Thiotriphosphate) ,Receptors, Serotonin ,Adenylyl Cyclase Inhibitors ,Adenylate Cyclase Toxin ,Guanosine Triphosphate - Abstract
The 5-hydroxytryptamine1A receptor (5-HT1AR) is a G-protein-coupled receptor negatively coupled to adenylyl cyclase (AC). We have studied the functional domains of 5-HT1AR using synthetic peptides to block or mimic receptor function. The entire second intracellular loop (5-HT1AR-i2) and the carboxyl end of the third intracellular loop (5-HT1AR-i3-C) strongly inhibited forskolin-stimulated AC activity. These effects were not additive with those of 5-HT. Like 5-HT, the peptides 5-HT1AR-i3-C and -i2 weakly inhibited AIF4- and Mn2+ stimulated AC activity. 5-HT1AR binding assays indicated that peptides could interact with the same G-protein pool as the 5-HT1AR. 5-HT1AR-i3-C- and -i2-stimulated [35S]guanosine 5'-O-(thiotriphosphate) binding on Go/Gi proteins. Only 5-HT1AR-i3-C partially adopted an alpha-helical conformation in solution. These data show that different domains in the 5-HT1AR second and third intracellular loops can couple to and activate Gi proteins in order to mediate AC inhibition. Peptide-induced AC inhibition was not sensitive to pertussis toxin as opposed to the 5-HT1AR-mediated effect. Our data show that the 5-HT1AR and the 5-HT1AR peptides activate Gi proteins in a slightly different manner.
- Published
- 1994
36. L-nitroarginine, an inhibitor of NO synthase, dramatically worsens limbic epilepsy in rats
- Author
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G, Rondouin, J, Bockaert, and M, Lerner-Natoli
- Subjects
Male ,Kainic Acid ,Blood Pressure ,Electroencephalography ,Amygdala ,Arginine ,Nitroarginine ,Injections ,Rats ,Rats, Sprague-Dawley ,Status Epilepticus ,Limbic System ,Animals ,Epilepsy, Generalized ,Amino Acid Oxidoreductases ,Nitric Oxide Synthase - Abstract
During status epilepticus provoked by an intra-amygdala injection of kainic acid, the severity of seizures and of consequent neuronal damage was considerably increased in rats treated with L-NOARG, at a dose which completely inhibited NO synthesis. We propose that the effects of L-NOARG could be related to the loss of a retrograde inhibition exerted by NO on NMDA receptors. The complete suppression of NO formation in the brain finally facilitated the development and the generalization of seizures and their neurotoxic consequences.
- Published
- 1993
37. Mutagenesis of the amino-terminal glycine to alanine in Gs alpha subunit alters beta gamma-dependent properties and decreases adenylylcyclase activation
- Author
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R, van der Neut, C, Pantaloni, I, Nebout, J, Bockaert, and Y, Audigier
- Subjects
Cholera Toxin ,Transcription, Genetic ,Macromolecular Substances ,Molecular Sequence Data ,Glycine ,Myristic Acid ,Polymerase Chain Reaction ,Cell Line ,GTP-Binding Proteins ,Receptors, Adrenergic, beta ,Centrifugation, Density Gradient ,Animals ,RNA, Messenger ,Adenosine Diphosphate Ribose ,Alanine ,Base Sequence ,Cell Membrane ,Isoproterenol ,Enzyme Activation ,Kinetics ,Oligodeoxyribonucleotides ,Guanosine 5'-O-(3-Thiotriphosphate) ,Protein Biosynthesis ,Mutagenesis, Site-Directed ,Myristic Acids ,Protein Processing, Post-Translational ,Adenylyl Cyclases ,Plasmids - Abstract
Proteolytic removal and genetic deletion of the amino-terminal domain of G protein alpha subunit have shown that this region is necessary for interaction with beta gamma subunits. In the alpha subunits which undergo myristoylation, myristoylation of the amino-terminal glycine modulates the affinity of alpha subunit for the beta gamma complex. To determine the role of the same glycine in nonmyristoylated alpha subunits, we substituted it for alanine in Gs alpha and characterized the properties of the mutated chain G2A Gs alpha. The mutant could still bind guanosine 5'-(3-O-thio)triphosphate (GTP gamma S) as revealed by its resistance to trypsin proteolysis and was able to interact with the membrane. However, G2A Gs alpha was a poor substrate for cholera toxin-catalyzed ADP-ribosylation either in the soluble form or when membrane-associated. Addition of beta gamma subunits increased the sedimentation rate of G2A Gs alpha in sucrose gradients. Binding experiments performed on cyc- membranes reconstituted by G2A Gs alpha showed that the GTP-induced shift of isoproterenol affinity for the beta-adrenergic receptors was reduced. On the same membranes, isoproterenol, GTP gamma S and NaF were 2-fold less effective for activating adenylylcyclase when compared to cyc- membranes reconstituted by Gs alpha. This differential stimulation of adenylylcyclase was not due to an affinity change for the effector but to a decrease in the maximal activation. Thus the G2A substitution affected beta gamma-dependent properties on reconstituted membranes such as receptor coupling and cholera toxin-catalyzed ADP-ribosylation and we propose that the decreased activation of adenylylcyclase might result from the same defect. Although not essential for association with beta gamma subunits, the amino-terminal glycine of nonmyristoylated Gs alpha might play a modulatory role in this interaction.
- Published
- 1993
38. Metabotropic glutamate receptors: an original family of G protein-coupled receptors
- Author
-
J. Bockaert, Jean-Philippe Pin, and L. Fagni
- Subjects
Pharmacology ,Metabotropic glutamate receptor 5 ,musculoskeletal, neural, and ocular physiology ,Metabotropic glutamate receptor 4 ,Metabotropic glutamate receptor 7 ,Metabotropic glutamate receptor 6 ,Brain ,Biology ,nervous system ,Biochemistry ,Receptors, Glutamate ,Metabotropic glutamate receptor ,GTP-Binding Proteins ,Type C Phospholipases ,mental disorders ,Metabotropic glutamate receptor 1 ,Animals ,Pharmacology (medical) ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,Protein Binding - Abstract
In 1985, we discovered a new glutamate receptor which was coupled to phospholipase C via a G protein and which was later termed metabotropic glutamate receptor (mGluR). In this review, both the diversity of mGluRs and the cellular events they control are discussed, as well as their roles in physiological regulation and brain function.
- Published
- 1993
39. Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons
- Author
-
H, Ansanay, M, Sebben, J, Bockaert, and A, Dumuis
- Subjects
Neurons ,Mice ,Tectum Mesencephali ,Zinc ,Cations, Divalent ,Heparin ,Receptors, Serotonin ,Cyclic AMP ,Animals ,Protein Kinase Inhibitors ,Protein Kinases ,Cells, Cultured ,Signal Transduction - Abstract
Exposure of mouse colliculi neurons to selective 5-hydroxytryptamine (5-HT)4 agonists was accompanied by a rapid desensitization of the receptor-stimulated adenylyl cyclase response. Half-maximal desensitization occurred after 2 min. Only exposure of neurons to selective 5-HT4 agonists led to a potent desensitization of the 5-HT4-mediated response. Neurons exposed to other agents, like isoproterenol, vasoactive intestinal peptide, or forskolin, that increase cAMP levels did not undergo any desensitization of 5-HT4 receptors. Activation of protein kinase A with either 8-bromo-cAMP or dibutyryl-cAMP or application of inhibitors of protein kinase A-dependent phosphorylation did not change the rate of 5-HT4-induced desensitization. No shift to lower potency of 5-HT4 agonists in the concentration-response curve was observed. These results suggest that 5-HT4 receptor agonists induced homologous but not cAMP-mediated heterologous desensitization. A good correlation was found between the affinities of nine 5-HT4 agonists and their abilities to desensitize the adenylyl cyclase response. This may indicate that homologous desensitization is a function of the mean occupancy time of the receptors by agonists. When permeabilized neurons were loaded with heparin, an inhibitor of the beta-adrenergic receptor kinase (beta ARK), 5-HT4 receptor desensitization was reduced by 30-40%. Interestingly, Zn2+, an other inhibitor of beta ARK, totally prevented 5-HT4-induced desensitization. Pretreatment of neurons with concanavalin A, reported to inhibit sequestration of beta-adrenergic receptors from the cell surface, reduced the desensitization process by 70%. These data suggest that both sequestration and phosphorylation by beta ARK, or another specific agonist-dependent receptor kinase, are involved in homologous desensitization of 5-HT4 receptors coupled to adenylyl cyclase.
- Published
- 1992
40. Nitric oxide-induced blockade of NMDA receptors
- Author
-
O, Manzoni, L, Prezeau, P, Marin, S, Desagher, S, Deshager, J, Bockaert, and L, Fagni
- Subjects
medicine.medical_specialty ,N-Methylaspartate ,Neuroscience(all) ,Endogeny ,In Vitro Techniques ,Nitric Oxide ,Receptors, N-Methyl-D-Aspartate ,Nitric oxide ,chemistry.chemical_compound ,Mice ,Internal medicine ,medicine ,Animals ,Patch clamp ,Long-term depression ,Cyclic GMP ,Sodium Nitrite ,Chemistry ,General Neuroscience ,Glutamate receptor ,N-Nitrosopyrrolidine ,Electrophysiology ,Endocrinology ,nervous system ,Cell culture ,Molsidomine ,Biophysics ,NMDA receptor ,Calcium ,Nitroso Compounds - Abstract
We studied the effects of nitric oxide (NO)-producing agents on N-methyl-d-aspartate (NMDA) receptor activation in cultured neurons. 3-Morpholinosydnonimine (SIN-1) blocked both NMDA-induced currents and the associated increase in intracellular Ca 2+ . The actions of SIN-1 were reversible and suppressed by hemoglobin. A degraded SIN-1 solution that did not release NO was unable to block NMDA receptors. This showed that the SIN-1 effects were due to NO and not to another breakdown product. Similar results were obtained with 1-nitrosopyrrolidine(an NO-containing drug) and with NO released from NaNO 2 . Pretreatment with hemoglobil potentiated NMDA-induced effects, demonstrating that endogenous NO modulates NMDA receptors. Since NMDA receptor activation induces NO synthesis, these results suggest a feedback inhibition of NMDA receptors by NO under physiological condition.
- Published
- 1992
41. Differential G protein-mediated coupling of D2 dopamine receptors to K+ and Ca2+ currents in rat anterior pituitary cells
- Author
-
P.M. Lledo, J. Bockaert, V. Homburger, and J.-D. Vincent
- Subjects
medicine.medical_specialty ,Potassium Channels ,G protein ,Dopamine ,chemistry.chemical_element ,Biology ,Calcium ,Pertussis toxin ,Membrane Potentials ,Receptors, Dopamine ,Anterior pituitary ,GTP-Binding Proteins ,Pituitary Gland, Anterior ,Internal medicine ,medicine ,Animals ,Receptor ,Adenosine Diphosphate Ribose ,General Neuroscience ,Cell Membrane ,Rats ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Dopamine receptor ,Biophysics ,Immunologic Techniques ,Potassium ,Calcium Channels ,Signal transduction ,Ion Channel Gating ,medicine.drug ,Signal Transduction - Abstract
In anterior pituitary cells, dopamine, acting on D 2 dopamine receptors, concomitantly reduces calcium currents and increases potassium currents. These dopamine effects require the presence of intracellular GTP and are blocked by pretreatment of the cells with pertussis toxin, suggesting that one or more G protein is involved. To identify the G proteins involved in coupling D 2 receptors to these currents, we performed patch-clamp recordings in the whole-cell configuration using pipettes containing affinity-purified polyclonal antibodies raised against either G oα , G 3α , or G i1,2α . Dialysis with G oα antiserum significantly reduced the inhibition of calcium currents induced by dopamine, while increase of potassium currents was markedly attenuated only by G i3α antiserum. We therefore conclude that in pituitary cells, two different G proteins are involved in the signal transduction mechanism that links D 2 receptor activation to a specific modulation of the four types of ionic channels studied here.
- Published
- 1992
42. Specific antibodies against Go isoforms reveal the early expression of the Go2 alpha subunit and appearance of Go1 alpha during neuronal differentiation
- Author
-
B, Rouot, N, Charpentier, C, Chabbert, J, Carrette, R, Zumbihl, J, Bockaert, and V, Homburger
- Subjects
Electrophoresis ,Neurons ,Macromolecular Substances ,Immunoblotting ,Molecular Sequence Data ,Brain ,Cell Differentiation ,DNA ,Antibodies ,Mice ,Neuroblastoma ,Fetus ,Antibody Specificity ,GTP-Binding Proteins ,Tumor Cells, Cultured ,Animals ,Amino Acid Sequence ,Rabbits - Abstract
We have previously identified two isoforms of Go alpha in membranes of N1E-115 neuroblastoma cells, using an antibody raised against the purified Go alpha subunit; one isoform of the Go alpha subunit (pI 5.80) is present in undifferentiated cells, whereas a more acidic isoform (pI 5.55) appears during differentiation [J. Neurochem. 54:1310-1320 (1990)]. Recently, the Go alpha gene has been shown to encode, by alternative splicing, two polypeptides, Go1 alpha and Go2 alpha, which differ only in their carboxyl-terminal part. To determine unambiguously whether the two Go alpha subunits detected in neuroblastoma cells were actually the products of different mRNAs, rabbit polyclonal antibodies were generated against synthetic peptides (amino acids 291-302) of both sequences. Specificity of the two affinity-purified antipeptide antibodies was assessed on Western blots by comparing their immunoreactivities with those of other G alpha antibodies. On a blotted mixture of purified brain guanine nucleotide-binding proteins, the anti-alpha o1 and anti-alpha o2 peptide antibodies only recognized the 39-kDa Go alpha subunit. Furthermore, the immunological recognition of brain membranes from 15-day-old mouse fetuses by antipeptide antibodies could be specifically blocked by addition of the corresponding antigen. When membrane proteins from differentiated neuroblastoma cells and mouse fetus brain were blotted after two-dimensional gel electrophoresis, the anti-alpha o1 and anti-alpha o2 peptide antibodies labeled a 39-kDa subunit focused at a pI value of 5.55 or 5.80, respectively. Study of the ontogenesis of both Go alpha subunits revealed the predominance of Go2 alpha in the frontal cortex at day 15 of gestation. Thereafter, there was a progressive decline of the Go2 alpha polypeptide to a very low level, concomitant with an increase in the Go1 alpha protein, which plateaued about 15 days after birth to a level 8 times higher than at gestational day 15. Similarly, on neuroblastoma cells, the Go2 alpha subunit was almost exclusively present in undifferentiated cells, and differentiation induced the appearance of the Go1 alpha subunit, with a reduction in the amount of Go2 alpha polypeptide. Thus, the evolution of the two Go alpha subunits during cell differentiation, unambiguously identified with specific antibodies, suggests that neuronal differentiation is responsible for the on/off switch of the expression of the Go alpha isoforms and indicates that Go1 alpha, rather than Go2 alpha, is involved in neurotransmission.
- Published
- 1992
43. Coupling of receptors to G proteins, pharmacological implications
- Author
-
J, Bockaert
- Subjects
Binding Sites ,GTP-Binding Proteins ,Humans ,Membrane Proteins ,Receptors, Cell Surface ,Receptors, Nicotinic ,Ligands ,Receptors, GABA-A ,Protein Binding - Abstract
There are four main classes of membrane-bound receptors: receptors which are also enzymes (tyrosine protein-kinase or guanylate cyclase), receptor channels, receptors coupled to G proteins (GTP binding proteins) and receptors with unknown transduction mechanisms. Receptors coupled to G proteins which have been cloned, constitute a superfamily of proteins containing seven hydrophobic transmembrane helices. The binding site of the ligand is within the hydrophobic core of the protein and the domain of interaction of the G proteins is constituted by the N- and C-terminal parts of the third intracellular loop, plus the C-terminal tail, adjacent to the transmembrane VII. G proteins themselves are also members of another superfamily. These proteins have highly conserved domains constituting the GTP binding site and they interact with the receptors by their C-terminal parts. Compounds such as mastoparan, substance P and 48/80 directly stimulate G proteins, an action which probably mediates their exocytotic properties. A high degree of homologies between G protein-linked receptors explains the non-specificity of some antagonists (like beta-adrenergic blocking agents on 5-HT1 receptors). The discovery of new members of the G protein-linked receptors which have not yet been pharmacologically characterized, raises the problem of receptor classification.
- Published
- 1991
44. 5-HT1A-sensitive adenylyl cyclase of rodent hippocampal neurons: effects of antidepressant treatments and chronic stimulation with agonists
- Author
-
A, Varrault, V, Leviel, and J, Bockaert
- Subjects
Clorgyline ,Mice ,Serotonin ,Pyrimidines ,Fluoxetine ,Receptors, Serotonin ,Adenylyl Cyclase Inhibitors ,Indomethacin ,Animals ,Hippocampus ,Antidepressive Agents ,Cells, Cultured - Abstract
The effects of chronic treatment with desimipramine (a tricyclic antidepressant), fluoxetine [a specific 5-hydroxytryptamine (5-HT) uptake inhibitor], clorgyline (a specific monoamine oxydase inhibitor of A type), ipsapirone (a specific 5-HT1A receptor agonist) as well as electroconvulsive shock treatment were investigated on rat hippocampal 5-HT1A receptors negatively coupled to adenylyl cyclase. Drugs were injected intraperitoneally in rats for 2 or 3 weeks, and biochemical determinations were made 4 to 72 hr after the final dose. Chronic treatments with desimipramine, ipsapirone and fluoxetine did not induce any change in the 5-HT1A-induced inhibition of the adenylyl cyclase activity. In contrast, chronic treatment with clorgyline and electroconvulsive shock treatment induced a slight but significant reduction of 5-HT's ability to inhibit hippocampal adenylyl cyclase. This indicates that, at least in hippocampal neurons, the 5-HT1A receptor coupled to adenylyl cyclase is not easily desensitized. This was verified in vitro on murine hippocampal neurons in culture, by measuring the effects of intense stimulation (1 and 2 hours), with 5-HT, ipsapirone and 8-hydroxy-2-(di-n-propylamino)tetralin. Indeed, such stimulations did not significantly affect the 5-HT1A receptor-induced inhibition of cAMP production in these hippocampal neurons in culture. Our results indicate that it is not the post-synaptic 5-HT1A receptor of hippocampus that is modified during antidepressant treatments, at least at the level of its coupling to adenylyl cyclase.
- Published
- 1991
45. Intracellular and Intercellular Messengers Produced by Metabotropic (Qp), AMPA, and NMDA Excitatory Amino Acid Receptors
- Author
-
Aline Dumuis, Mireille Lafon-Cazal, Michèle Sebben, Olivier J. Manzoni, Laurent Fagni, J. Bockaert, Jean-Philippe Pin, Philippe Marin, and Fritz Sladeczek
- Subjects
Metabotropic receptor ,nervous system ,Chemistry ,G protein ,Glutamate receptor ,NMDA receptor ,Kainate receptor ,AMPA receptor ,Receptor ,Long-term depression ,Cell biology - Abstract
Glutamate (Glu) receptors can be classified into two main classes: the ionotropic receptor class and the G protein-coupled receptor class (G protein = GTP-binding protein). The first class includes the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate (KA) receptors. Recently, several clones (at least six) encoding for functional AMPA and one clone encoding for functional KA receptors have been sequenced [1–5].
- Published
- 1991
46. The transduction signalling protein Go during embryonic development of Drosophila melanogaster
- Author
-
A, Guillén, M, Sémériva, J, Bockaert, and V, Homburger
- Subjects
Embryonic and Fetal Development ,Drosophila melanogaster ,GTP-Binding Proteins ,Molecular Sequence Data ,Animals ,Amino Acid Sequence ,Immunohistochemistry ,Precipitin Tests ,Signal Transduction - Abstract
G proteins are heterotrimeric proteins that play a key role in signalling transduction conveying signals from cell surface receptors to intracellular effector proteins. In particulate preparations from Drosophila melanogaster embryos, only one substrate of 39,000-40,000 molecular weight could be ADP-ribosylated with pertussis toxin. This substrate reacted in immunoblotting and immunoprecipitation experiments with a polyclonal antibody directed against the carboxy-terminal sequence of the alpha subunit of the mammalian Go protein. The Drosophila Go alpha protein was present at all stages of embryonic development; however, its expression markedly increased after 10 h embryogenesis, a period of time during which there is an active development of axonal tracts. Immunolocalization on whole mount embryos has indicated that this protein is principally localized in the CNS and is mainly restricted to the neuropil without any labelling of the cell bodies. In contrast, all the axon tracts of the CNS appeared to be highly labelled. The distribution of the Go alpha protein was also examined in several neurogenic mutants. The Go alpha protein expression was not altered in any of them but the pattern of labelling was disorganized as was the neuronal network. These results suggest a possible role for the Go protein during axonogenesis.
- Published
- 1991
47. Triggering of Arachidonic Acid Release from Mature Striatal Neurons by Associative Stimulation of Ionotropic (AMPA) and Quisqualate Receptors Coupled to Phospholipase C (Qp)
- Author
-
J. Bockaert, Michèle Sebben, Aline Dumuis, J. P. Pin, and K. Oomagari
- Subjects
Postsynaptic potential ,Chemistry ,Synaptic plasticity ,Excitatory postsynaptic potential ,LTP induction ,NMDA receptor ,Long-term potentiation ,Stimulation ,AMPA receptor ,Neuroscience - Abstract
It has been proposed that memory is encoded in the brain through a permanent increase in strength of synapses due to an associative stimulation of pre- and post-synaptic activity (Eccles 1953; Hebb 1949). This is why the discovery of associative long-term potentiation (LTP) has been so attractive (for reviews, see Kennedy 1989; Nicoll et al. 1988). In some glutamatergic synapses, high frequency presynaptic stimulation — but also weak stimulation associated with depolarization of the post-synaptic membrane — produces LTP, i.e., an enhancement of the transmission efficacy that could last hours to weeks. The main events required for LTP induction are a presynaptic stimulation, which is needed for glutamate (Glu) release, associated with a postsynaptic depolarization produced either by a sustained high level of transmitter release or by stimulation of nearby excitatory synapses (Kennedy 1989). The discovery that the full activation of N-methyl-D-aspartate (NMDA) glutamatergic receptors is by itself an associative process requiring presynaptic stimulation to release the agonist glutamate and postsynaptic depolarisation to suppress the Mg++ blockade of its channel (Nowak et al. 1984) indicates a primordial role for NMDA receptors in synaptic plasticity. Such a role is clearly demonstrated by the blockade of LTP by NMDA receptor antagonists.
- Published
- 1991
48. [Monoclonal antibodies obtained against G-protein epitopes: comparison of immunoreactions seen in the brain, retina and striated muscular tissue]
- Author
-
S, Peraldi-Roux, P, Mangeat, B, Rouot, J, Oliver, S, Herbute, P, Brabet, V, Homburger, M, Toutant, J, Bockaert, and J, Gabrion
- Subjects
Epitopes ,Mice ,Mice, Inbred BALB C ,Nerve Fibers ,Muscles ,Animals ,Antibodies, Monoclonal ,Fluorescent Antibody Technique ,Enzyme-Linked Immunosorbent Assay ,Nerve Tissue Proteins ,Retina - Abstract
Monoclonal antibodies have been obtained against a purified fraction of brain G proteins containing the Gi alpha, G0 alpha, G beta, and G gamma subunits. After characterization, two monoclonal antibodies have been used to detect the cellular distribution of the two epitopes in neural, retinal and muscular tissues: ELISA, cross-dot and Western blot demonstrated that F.IV.5 is an anti-G beta antibody specific for the 36 kDa beta-subunit. ELISA, cross-dot and immunocytochemical distribution of the epitopes recognized by F.VII.9 suggested that this antibody recognizes epitopes which are also detected with polyclonal anti-G0 alpha antibodies. With both monoclonal antibodies, we confirmed that G proteins demonstrated a sub-membranous distribution as well as extensively cytoplasmic, axoplasmic or sarcoplasmic distributions in different cell types.
- Published
- 1991
49. Rapid, sensitive, and simple method for quantification of both neurotoxic and neurotrophic effects of NMDA on cultured cerebellar granule cells
- Author
-
M, Didier, M, Heaulme, P, Soubrié, J, Bockaert, and J P, Pin
- Subjects
Neurons ,Aspartic Acid ,N-Methylaspartate ,Cell Survival ,Glutamic Acid ,Culture Media ,Mice ,Glutamates ,Microscopy, Fluorescence ,Cerebellum ,Potassium ,Animals ,Dizocilpine Maleate ,Cells, Cultured - Abstract
A simple and sensitive method adapted from the staining of living cells with fluorescein diacetate was developed to rapidly estimate the number of living cells remaining in a culture dish 24 hr after a few min of NMDA treatment of cerebellar neurons. This method consists of the measurement, after cell lysis, of the total amount of fluorescein produced from fluorescein diacetate by the living granule cells present in each culture dish. We show that this method can also be used to quantify the survival effect of chronic exposure of granule cells to either K+ or NMDA. In both cases, the fluorescence measured was found to be proportional to the number of fluorescein-labelled cells counted under a fluorescence microscope, indicating that the present method can be used to quantify both toxic and trophic effects of NMDA on cerebellar granule cells. This study confirms that these two NMDA effects occur at the same NMDA concentration, and both are inhibited by MK 801 in the same concentration range. We showed, moreover, that granule neurons developed in the presence of NMDA are much less sensitive to NMDA toxicity than neurons developed in K(+)-enriched medium.
- Published
- 1990
50. Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives
- Author
-
J, Bockaert, M, Sebben, and A, Dumuis
- Subjects
Male ,Serotonin ,Indoles ,Guinea Pigs ,Tropisetron ,In Vitro Techniques ,Bridged Bicyclo Compounds, Heterocyclic ,Hippocampus ,Enzyme Activation ,Bridged Bicyclo Compounds ,Structure-Activity Relationship ,Spiperone ,Receptors, Serotonin ,Benzamides ,Animals ,Adenylyl Cyclases ,Signal Transduction - Abstract
Adult guinea pig hippocampal membranes contain two 5-hydroxytryptamine (5-HT) receptors positively coupled with an adenylate cyclase. One is a typical 5-HT1A receptor and the second is a nonclassical 5-HT receptor that we previously proposed to call 5-HT4. Here, we show that 4-amino-5-chlor-2-methoxy-benzamide derivatives are agonists of 5-HT4 receptors in guinea pig hippocampal membranes. Their effects on the adenylate cyclase of these membranes are not additive with those of 5-HT but are additive with those of RU 24969, a typical 5-HT1 agonist. The effects of benzamides, as well as those of 5-HT, on 5-HT4 receptors are not blocked by 5-HT1, 5-HT2, or 5-HT3 antagonists except ICS 205 903, which does so with a low affinity (1 microM). The potency of benzamides (cisapride greater than BRL 24924 greater than zacopride greater than BRL 20627 greater than metoclopramide) is similar to their effect of 5-HT4 receptors positively coupled with an adenylate cyclase of fetal mouse colliculi neurons.
- Published
- 1990
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