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Orexin-Induced Apoptosis: The Key Role of the Seven-Transmembrane Domain Orexin Type 2 Receptor

Institut National de la Santé et de la Recherche Médicale, Unité 773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, and Université Paris 7 Denis Diderot, site Bichat, F-75018, Paris, France

Address all correspondence and requests for reprints to: Thierry Voisin, Institut National de la Santé et de la Recherche Médicale, Unité 773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, BP 416, F-75018, Paris, France; Université Paris 7 Denis Diderot, site Bichat, BP 416, F-75018, Paris, France. E-mail: tvoisin{at}bichat.inserm.fr.

Orexin-A and orexin-B are regulatory peptides involved in the control of feeding, sleep-wakefulness, and exerting various endocrine and metabolic actions. Recently we demonstrated that orexins, acting at OX₁ receptor (OX₁R), are proapoptotic peptides. The aim of this study was to investigate the role of the receptor subtype OX₂R in the control of apoptosis. Orexins caused a caspase-dependent cell death by apoptosis and a drastic cell growth inhibition in Chinese hamster ovary cells transfected with OX₂R cDNA. On addition of either orexin (10^–6 M) for 48 h, apoptosis was demonstrated by DNA fragmentation, chromatin condensation, annexin-V binding, and activation of caspase-3 and caspase-9. Orexins were active on apoptosis and cell growth inhibition in the range of concentrations between 10^–10 and 10^–5 M with an EC₅₀ of 5 x 10^–8 M peptides. No effect of orexins could be detected in parental Chinese hamster ovary cells. A rat pancreatic acinar cell line, AR42J, which expresses OX₂R but not OX₁R, also underwent growth suppression and apoptosis on treatment with orexins. Suppression of AR42J cell growth by 10^–6 M orexin was more than 75% after 24 h. Induction of annexin-V-labeled AR42J cell number was dose dependent, with EC₅₀ of 5.1 x 10^–8 M orexin-A and 9.8 x 10^–8 M orexin-B. The OX₂R agonist [Ala (11), D-Leu (15)]orexin-B promoted effects on cell growth and apoptosis, which were similar to those elicited by orexins. The OX₁R antagonist SB33487 did not alter orexin-induced inhibition of growth or orexin-induced stimulation of apoptosis in AR42J cells. For the first time, we provide functional and pharmacological evidence for a role of the OX₂R in orexin-induced apoptosis.

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				T. Voisin, A. El Firar, C. Rouyer-Fessard, V. Gratio, and M. Laburthe A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism FASEB J, June 1, 2008; 22(6): 1993 - 2002. [Abstract] [Full Text] [PDF]