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 1D Autoreceptors through Reactive Oxygen Species and Tumor Necrosis Factor- Signaling in Neuronal Cells
a Institut André Lwoff-Institut Pasteur, CNRS FRE 2937, Laboratoire Différenciation Cellulaire et Prions, Villejuif Cedex, France b Pharma Research Department, F. Hoffman-La-Roche Ltd., Basel, Switzerland c Service de Biochimie, EA3621 Hôpital Lariboisière, Faculté de Pharmacie, Université Paris V, Paris, France
Key Words: bioamine metabolism • reactive oxygen species • TNF-  • autoreceptor signaling • neuronal differentiation
Address for correspondence: Dr. Benoît Schneider, Institut André Lwoff, CNRS FRE 2937, Laboratoire Différenciation Cellulaire et Prions, 7, rue Guy Môquet, 94801 Villejuif Cedex, France. Voice: +33-1-49-58-33-31; fax: +33-1-49-58-33-29. e-mail: bschneid{at}vjf.cnrs.fr
Homeostasis of the central nervous system relies on the proper integration of cell-signaling pathways recruited by a variety of neuronal and non-neuronal factors, with the aim of tightly controlling neurotransmitter metabolism, storage, and transport. We took advantage of the 1C11 neuroectodermal cell line, endowed with the capacity to selectively differentiate into serotonergic (1C115–HT) or noradrenergic (1C11NE) neurons, to identify functional targets of serotonin (5-hydroxytryptamine [5–HT]) and norepinephrine (NE) autoreceptors possibly involved in the control of neuronal functions. We demonstrate that 5-HT2B and adreno
1D receptors are coupled to reactive oxygen species (ROS) production through NADPH oxidase activation in 1C115–HT and 1C11NE neuronal cells, respectively. In the signaling cascade linking 5–HT2B receptors to NADPH oxidase, phospholipase A2-mediated arachidonic acid production is required for ROS synthesis. ROS, in turn, act as second message signals and control the activation of TACE (TNF- converting enzyme), a member of a disintegrin and metalloproteinase family. 5–HT2B and 1D receptor stimulation triggers TACE-dependent TNF- shedding in the surrounding milieu of 1C115–HT and 1C11NE cells. In these cells, shed TNF- triggers degradation of 5-HT and NE into 5-HIAA and MHPG, respectively. Finally, we observe that 5-HT2B and 1D receptor couplings to the NADPH oxidase-TACE cascade are strictly restricted to 1C11-derived progenies that have implemented a complete neuronal phenotype. Altogether, our data indicate that couplings of 5-HT2B and 1D autoreceptors to ROS and TNF- signaling control neurotransmitter metabolism in 1C11-derived neuronal cells. Eventually, we might explain the origin of oxidative stress and high level of TNF- in neurodegenerative diseases as a consequence of deviation of normal signaling pathways coupled to neurotransmitters.
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