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J. Biol. Chem., Vol. 281, Issue 2, 834-842, January 13, 2006

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G-protein-coupled OX₁ Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase^*

Sylwia Ammoun, Dan Lindholm¶, Hanna Wootz, Karl E. O. Åkerman||, and Jyrki P. Kukkonen1

From the Department of Neuroscience, Unit of Physiology, Uppsala University, SE-75123 Uppsala, Sweden, the Department of Neuroscience, Unit of Neurobiology, Uppsala University, SE-75123 Uppsala, Sweden, the ^¶Minerva Foundation Institute for Medical Research, FIN-00290 Helsinki, Finland, and the ^||A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70210 Kuopio, Finland

We have investigated the signaling of OX₁ receptors to cell death using Chinese hamster ovary cells as a model system. OX₁ receptor stimulation with orexin-A caused a delayed cell death independently of cytosolic Ca²⁺ elevation. The classical mitogen-activated protein kinase (MAPK) pathways, ERK and p38, were strongly activated by orexin-A. p38 was essential for induction of cell death, whereas the ERK pathway appeared protective. A pathway often implicated in the p38-mediated cell death, activation of p53, did not mediate the cell death, as there was no stabilization of p53 or increase in p53-dependent transcriptional activity, and dominant-negative p53 constructs did not inhibit cell demise. Under basal conditions, orexin-A-induced cell death was associated with compact chromatin condensation and it required de novo gene transcription and protein synthesis, the classical hallmarks of programmed (apoptotic) cell death. However, though the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethyl ketone (Z-VAD-fmk) fully inhibited the caspase activity, it did not rescue the cells from orexin-A-induced death. In the presence of Z-VAD-fmk, orexin-A-induced cell death was still dependent on p38 and de novo protein synthesis, but it no longer required gene transcription. Thus, caspase inhibition causes activation of alternative, gene transcription-independent death pathway. In summary, the present study points out mechanisms for orexin receptor-mediated cell death and adds to our general understanding of the role of G-protein-coupled receptor signaling in cell death by suggesting a pathway from G-protein-coupled receptors to cell death via p38 mitogen-/stress-activated protein kinase independent of p53 and caspase activation.

Received for publication, August 4, 2005 , and in revised form, November 2, 2005.

^* This work was supported by the European Union Contract QLG3-CT-2002-00826, the Cancer Research Fund of Sweden, the Lars Hierta Foundation, the Åke Wiberg Foundation, the Göran Gustafsson Foundation, the Novo Nordisk Foundation, the Mary, Åke and Hans Ländall Foundation, Uppsala University, the Academy of Finland, and the Sigrid Jusélius Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neuroscience, Unit of Physiology, Uppsala University, BMC, P. O. Box 572, SE-75123 Uppsala, Sweden. Tel.: 46-18-4714171; Fax: 46-18-501740; E-mail: jyrki.kukkonen{at}neuro.uu.se.

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