PT - JOURNAL ARTICLE AU - Daniela A. Eisinger AU - Rüdiger Schulz TI - Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinases Block Internalization of δ-Opioid Receptors AID - 10.1124/jpet.103.061788 DP - 2004 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 776--785 VI - 309 IP - 2 4099 - http://jpet.aspetjournals.org/content/309/2/776.short 4100 - http://jpet.aspetjournals.org/content/309/2/776.full SO - J Pharmacol Exp Ther2004 May 01; 309 AB - Translocation of G protein-coupled receptors (GPCRs) from the cell membrane to cytosol depends on the kind of ligand activating the receptor. This principle is clearly demonstrated for opioid receptors, because diverse opiate agonists rapidly induce receptor internalization, whereas morphine almost fails. We report here the impact of mitogen-activated protein (MAP) kinase isoforms extracellular signal-regulated kinase (ERK)1/2 on the internalization of δ-opioid receptors (DORs) expressed in human embryonic kidney (HEK)293 cells. Receptor activation by etorphine turned out to transiently phosphorylate ERK/MAP kinases and bring about DOR internalization within 20 min. In contrast, prolonged exposure of HEK293 cells to morphine excited persistent phosphorylation of ERK/MAP kinases, and those cells failed to internalize the opioid receptor. When ERK/MAP kinase phosphorylation was blocked by 2′-Amino-3′-methoxyflavone (PD98059), morphine gained the ability to strongly induce DOR endocytosis. The importance of activated MAP kinases for DOR internalization is further demonstrated by glutamate and paclitaxel because these substances induce phosphorylation of ERK1/2 and concomitantly prevent DOR sequestration by etorphine. In addition, receptor internalization by morphine was facilitated by inhibition of protein kinase C and opioid-mediated transactivation of epidermal growth factor receptor (EGFR), both activating ERK/MAP kinases by opioids. The mechanism affording DOR internalization by PD98059 may relate to arrestin, which uncouples GPCRs and thus triggers receptor internalization. Arrestin considerably translocates toward the cell membrane upon DOR activation by morphine in presence of the MAP kinase blocker, but it fails in the absence of PD98059. We conclude that ERK/MAP kinase activity prevents opioid receptor desensitization and sequestration by blocking arrestin 2 interaction with activated DORs. The American Society for Pharmacology and Experimental Therapeutics