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 G␣ 13 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. G-protein-coupled receptors (GPCRs)2 constitute the largest family of cell surface transmembrane proteins (1); they are activated by a wide variety of natural ligands, and pharmacological alteration of their signaling constitutes one of the most successful approaches to the treatment of human disease, which makes GPCRs the most targeted protein superfamily in pharmaceutical research (2). We recently presented a screening system able to discriminate protective and detrimental receptors involved in oxidative stress (3) to identify targets for the multitude of human diseases caused or aggravated by oxidative stress. In this proof-of-concept study, we noticed that the relative mRNA content of cytoprotective GPCRs (the most prominent being VPAC 2 , a receptor for the neuroprotective vasoactive intestinal peptide VIP) was increased in glutamate-resistant (HT22R) cells generated by repeated exposure of the parental cell line HT22 to high concentrations of glutamate and further propagation of the few surviving cells. HT22 cells are derived from embryonal mouse hippocampal cells and are considered to be a model system of cell death by oxidative stress. In this model system, increased extracellular glutamate blocks the gradientdriven glutamate/cysteine antiporter X c Ϫ , depleting the cells of cysteine. Cysteine is required for the synthesis of the important antioxidant glutathione, and the sequence of events after depletion of intracellular glutathione involves the activation of 12-lipoxygenase, the accumulation of in...
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