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Reactive oxygen species-dependent TNF- converting enzyme activation through stimulation of 5-HT_2B and _1D autoreceptors in neuronal cells

Mathéa Pietri^*, Benoît Schneider^*,1, Sophie Mouillet-Richard^*, Myriam Ermonval^*, Vincent Mutel, Jean-Marie Launay and Odile Kellermann^*

^* Institut André Lwoff-Institut Pasteur, CNRS UPR 1983, Laboratoire de Différenciation Cellulaire et Prions, Villejuif Cedex, France;
Pharma Research Department, F. Hoffmann-La-Roche Ltd., Basel, Switzerland; and
Service de Biochimie, EA3621 Hôpital Lariboisière, Faculté de Pharmacie, Université Paris V, Paris, France

¹ Correspondence: Différenciation Cellulaire et Prions, Institut André Lwoff, CNRS UPR 1983, 7 rue Guy Môquet, 94801 Villejuif Cedex, France. E-mail: bschneid{at}vjf.cnrs.fr

A major determinant of neuronal homeostasis is the proper integration of cell signaling pathways recruited by a variety of neuronal and non-neuronal factors. By taking advantage of a neuroectodermal cell line (1C11) endowed with the capacity to differentiate into serotonergic (1C11^5-HT) or noradrenergic (1C11^NE) neurons, we identified serotonin (5-hydroxytryptamine, 5-HT)- and norepinephrine (NE)-dependent signaling cascades possibly involved in neuronal functions. First, we establish that 5-HT_2B receptors and _1D adrenoceptors are functionally coupled to reactive oxygen species (ROS) synthesis through NADPH oxidase activation in 1C11^5-HT and 1C11^NE cells. This observation constitutes the prime evidence that bioaminergic autoreceptors take part in the control of the cellular redox equilibrium in a neuronal context. Second, our data identify TACE (TNF- Converting Enzyme), a member of a disintegrin and metalloproteinase (ADAM) family, as a downstream target of the 5-HT_2B and _1D receptor-NADPH oxidase signaling pathways. Upon 5-HT_2B or _1D receptor stimulation, ROS fully govern TNF- shedding in the surrounding milieu of 1C11^5-HT or 1C11^NE cells. Third, 5-HT_2B and _1Dreceptor couplings to the NADPH oxidase-TACE cascade are strictly restricted to 1C11-derived progenies that have implemented a complete serotonergic or noradrenergic phenotype. Overall, these observations suggest that 5-HT_2B and _1D autoreceptors may play a role in the maintenance of neuron- and neurotransmitter-associated functions. Eventually, our study may have implications regarding the origin of oxidative stress as well as up-regulated expression of proinflammatory cytokines in neurodegenerative disorders, which may relate to the deviation of normal signaling pathways.—Pietri, M., Schneider, B., Mouillet-Richard, S., Ermonval, M., Mutel, V., Launay, J.-M., Kellermann, O. Reactive oxygen species-dependent TNF- converting enzyme activation through stimulation of 5-HT_2B and _1D autoreceptors in neuronal cells.

Key Words: bioaminergic autoreceptors • ROS signaling • metalloproteinase • neuronal differentiation • neuronal homeostasis

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