Reactive oxygen species-dependent TNF-alpha converting enzyme activation through stimulation of 5-HT2B and alpha1D autoreceptors in neuronal cells.
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 (1C115-HT) or noradrenergic (1C11NE) neurons, we identified serotonin (5-hydroxytryptamine, 5-HT)- and norepinephrine (NE)-dependent signaling cascades possibly involved in neuronal functions. First, we establish that 5-HT2B receptors and 1D adrenoceptors are functionally coupled to reactive oxygen species (ROS) synthesis through NADPH oxidase activation in 1C115-HT and 1C11NE 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-HT2B and 1D receptor-NADPH oxidase signaling pathways. Upon 5-HT2B or 1D receptor stimulation, ROS fully govern TNF- shedding in the surrounding milieu of 1C115-HT or 1C11NE cells. Third, 5-HT2B 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-HT2B 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.
Institut André Lwoff-Institut Pasteur, CNRS UPR 1983, Laboratoire de Différenciation Cellulaire et Prions, Villejuif Cedex, France.
Mathéa
M
Pietri
Benoît
B
Schneider
Sophie
S
Mouillet-Richard
Myriam
M
Ermonval
Vincent
V
Mutel
Jean-Marie
JM
Launay
Odile
O
Kellermann
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D004789:Enzyme Activation; D006706:Homeostasis; D051379:Mice; D019255:NADPH Oxidases / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000209:etiology; D009474:Neurons / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044346:Receptor, Serotonin, 5-HT1D / Q000502:physiology*; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D015398:Signal Transduction
D017660:Autoreceptors; D017382:Reactive Oxygen Species; D044346:Receptor, Serotonin, 5-HT1D; D044403:Receptor, Serotonin, 5-HT2B; D019255:NADPH Oxidases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse