Involvement of the N-methyl-D-aspartate receptor in neuronal cell death induced by cytotoxic T cell-derived secretory granules

Détails

ID Serval
serval:BIB_8F1E547D4C98
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Involvement of the N-methyl-D-aspartate receptor in neuronal cell death induced by cytotoxic T cell-derived secretory granules
Périodique
European Journal of Immunology
Auteur(s)
Malipiero  U., Heuss  C., Schlapbach  R., Tschopp  J., Gerber  U., Fontana  A.
ISSN
0014-2980 (Print)
Statut éditorial
Publié
Date de publication
10/1999
Volume
29
Numéro
10
Pages
3053-62
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Oct
Résumé
The mechanisms underlying neurotoxicity mediated by cytotoxic T lymphocytes (CTL) and their secretory granule proteins perforin and granzymes remain unclear. We evaluated the possible role of the neurotransmitter glutamate in cell death observed in differentiated neurons exposed to CTL-derived granules. Excitotoxicity induced by excessive concentrations of extracellular glutamate is associated with a rise in intracellular calcium and can lead to generation of NO through the activation of glutamatergic N-methyl-D-aspartate (NMDA) receptors. Consistent with an involvement of glutamate, we found that cell death in mature cerebral granule cells was inhibited by 65-80% by two NMDA receptor blockers (MK-801 and D-2-amino-5-phosphonovaleric acid) or a NO synthase blocker (N(G)-nitro-L-arginine methylester). Furthermore, neurons treated with secretory granules responded with a biphasic rise in the intracellular calcium concentration ([Ca2+]i). Whereas MK-801 did not interfere with the immediate rise of [Ca2+]i, the second wave of calcium accumulation starting at 40 min was delayed by 20 min and reduced in amplitude in the presence of MK-801. In immature, NMDA receptor-negative neurons, MK-801 prevented neither the cytotoxicity nor the calcium influx observed 5 min after addition of cytotoxic granules. The demonstration that NMDA receptors and NO are involved in granule-mediated killing of mature neurons opens new avenues in the treatment of neuronal cell death in CTL-mediated diseases such as viral encephalitis.
Mots-clé
2-Amino-5-phosphonovalerate/pharmacology Animals Calcium/immunology/metabolism Cell Death/immunology Cell Differentiation Cells, Cultured Cerebellum/cytology/immunology Cytoplasmic Granules/*immunology/metabolism Dizocilpine Maleate/pharmacology Enzyme Inhibitors/pharmacology Excitatory Amino Acid Antagonists/pharmacology Mice Mice, Inbred C57BL NG-Nitroarginine Methyl Ester/pharmacology Neurons/cytology/*immunology/*metabolism Nitric Oxide/immunology/metabolism Nitric Oxide Synthase/antagonists & inhibitors Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*physiology T-Lymphocytes, Cytotoxic/*immunology
Pubmed
Web of science
Création de la notice
24/01/2008 16:18
Dernière modification de la notice
03/03/2018 19:20
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