MU-OPIOID RECEPTOR ACTIVATES SIGNALING PATHWAYS IMPLICATED IN CELL-SURVIVAL AND TRANSLATIONAL CONTROL

The mu-opioid receptor mediates the analgesic and addictive properties of morphine. Despite the clinical importance of this G-protein-couple d receptor and many years of pharmacological research, few intracellul ar signaling mechanisms triggered by morphine and other mu-opioid agon ists have been described. We report that mu-opioid agonists stimulate three different effecters of a phosphoinositide 3-kinase (PI3K)-depend ent signaling cascade. By using a cell line stably transfected with th e mu-opioid receptor cDNA, we show that the specific agonist [D-Ala(2) ,N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO) stimulates the activity of A kt, a serine/threonine protein kinase implicated in protecting neurons from apoptosis, Activation of Akt by DAMGO correlates with its phosph orylation at serine 473, The selective PI3K inhibitors wortmannin and LY294002 blocked phosphorylation of this site, previously shown to be necessary for Akt enzymatic activity. DAMGO also stimulates the phosph orylation of two other downstream effecters of PI3K the p70 S6 kinase and the repressors of mRNA translation, 4E-BP1 and 4E-BP2. Upon mu-opi oid receptor stimulation, p70 S6 kinase is activated and phosphorylate d at threonine 389 and at threonine 421/serine 424, Phosphorylation of p70 S6 kinase and 4E-BP1 is also repressed by PI3K inhibitors as well as by rapamycin, the selective inhibitor of FRAP/mTOR, Consistent wit h these findings, DAMGO-stimulated phosphorylation of 4E-BP1 impairs i ts ability to bind the translation initiation factor eIF-4E. These res ults demonstrate that the p-opioid receptor activates signaling pathwa ys associated with neuronal survival and translational control, two pr ocesses implicated in neuronal development and synaptic plasticity.