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  • Title: delta-Opioid receptor-stimulated Akt signaling in neuroblastoma x glioma (NG108-15) hybrid cells involves receptor tyrosine kinase-mediated PI3K activation.
    Author: Heiss A, Ammer H, Eisinger DA.
    Journal: Exp Cell Res; 2009 Jul 15; 315(12):2115-25. PubMed ID: 19362548.
    Abstract:
    delta-Opioid receptor (DOR) agonists possess cytoprotective properties, an effect associated with activation of the "pro-survival" kinase Akt. Here we delineate the signal transduction pathway by which opioids induce Akt activation in neuroblastomaxglioma (NG108-15) hybrid cells. Exposure of the cells to both [D-Pen(2,5)]enkephalin and etorphine resulted in a time- and dose-dependent increase in Akt activity, as measured by means of an activation-specific antibody recognizing phosphoserine-473. DOR-mediated Akt signaling is blocked by the opioid antagonist naloxone and involves inhibitory G(i/o) proteins, because pre-treatment with pertussis toxin, but not over-expression of the G(q/11) scavengers EBP50 and GRK2-K220R, prevented this effect. Further studies with Wortmannin and LY294002 revealed that phophoinositol-3-kinase (PI3K) plays a central role in opioid-induced Akt activation. Opioids stimulate Akt activity through transactivation of receptor tyrosine kinases (RTK), because pre-treatment of the cells with inhibitors for neurotrophin receptor tyrosine kinases (AG879) and the insulin-like growth factor receptor IGF-1 (AG1024), but not over-expression of the Gbetagamma scavenger phosducin, abolished this effect. Activated Akt translocates to the nuclear membrane, where it promotes GSK3 phosphorylation and prevents caspase-3 cleavage, two key events mediating inhibition of cell apoptosis and enhancement of cell survival. Taken together, these results demonstrate that in NG108-15 hybrid cells DOR agonists possess cytoprotective properties mediated by activation of the RTK/PI3K/Akt signaling pathway.
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