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J. Biol. Chem., Vol. 283, Issue 11, 7074-7081, March 14, 2008

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The Constitutively Active Orphan G-protein-coupled Receptor GPR39 Protects from Cell Death by Increasing Secretion of Pigment Epithelium-derived Growth Factor^*

Sonja Dittmer, Mert Sahin, Anna Pantlen, Ambrish Saxena, Diamandis Toutzaris, Ana-Luisa Pina^¶, Andreas Geerts^||, Stefan Golz^||, and Axel Methner¹

From the Research Group Protective Signaling, Department of Neurology, Heinrich Heine Universität Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany, the Zentrum für Molekulare Neurobiologie Hamburg, Martinistrasse 52, 20251 Hamburg, Germany, the ^¶Neurobiology Research Group, Department of Neurosurgery, University Clinic of Regensburg, Franz-Josef Strauss Allee 11, 93053 Regensburg, Germany, and the ^||Institute for Target Research, Bayer HealthCare AG, 42096 Wuppertal, Germany

GPR39 is a constitutively active orphan G-protein-coupled receptor capable of increasing serum response element-mediated transcription. We found GPR39 to be up-regulated in a hippocampal cell line resistant against diverse stimulators of cell death and show that its overexpression protects against oxidative and endoplasmic reticulum stress, as well as against direct activation of the caspase cascade by Bax overexpression. In contrast, silencing GPR39 rendered cells more susceptible to cell death. An array analysis of transcripts induced by GPR39 revealed up-regulation of RGS16 (inhibitor of G-protein signaling 16), which suggested coupling to G₁₃ and induction of serum response element-mediated transcription by the small GTPase RhoA. In line with this, co-expression of GPR39 with RGS16, dominant-negative RhoA, or serum response factor abolished cell protection, whereas overexpression of the serum response factor protected from cell death. Further downstream the signaling cascade, GPR39 overexpression leads to increased secretion of the cytoprotective pigment epithelium-derived growth factor (PEDF). Medium conditioned by cells overexpressing GPR39 contained 4-fold more PEDF, and when stripped off it lost most but not all of its protective properties. We conclude that GPR39 is a novel inhibitor of cell death, which might represent a therapeutic target with implications for processes involving apoptosis and endoplasmic reticulum stress like cancer, ischemia/reperfusion injury, and neurodegenerative disease.

Received for publication, May 25, 2007 , and in revised form, December 17, 2007.

^* This work was supported by Deutsche Forschungsgemeinschaft Graduiertenkolleg 255 and 1033, the Dr. Kurt und Irmgard Meister-Stiftung, and the Stiftung für Alternsforschung. 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 Neurology, Heinrich Heine Universität Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Tel.: 49-172-44510481; Fax: 49-40-42803-5101; E-mail: axel.methner{at}gmail.com.

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