PT  - JOURNAL ARTICLE
AU  - Belcheva, Mariana M.
AU  - Tan, Yun
AU  - Heaton, Virginia M.
AU  - Clark, Amy L.
AU  - Coscia, Carmine J.
TI  - μ Opioid Transactivation and Down-Regulation of the Epidermal Growth Factor Receptor in Astrocytes: Implications for Mitogen-Activated Protein Kinase Signaling
AID  - 10.1124/mol.64.6.1391
DP  - 2003 Dec 01
TA  - Molecular Pharmacology
PG  - 1391--1401
VI  - 64
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/64/6/1391.short
4100  - http://molpharm.aspetjournals.org/content/64/6/1391.full
SO  - Mol Pharmacol2003 Dec 01; 64
AB  - Astroglia are a principal target of long-term μ antiproliferative actions. The mitogen-activated protein (MAP) kinase known as extracellular signal-regulated kinase (ERK), is a key mediator of cell proliferation. In studies on the mechanism of short- and long-term μ opioid regulation of the ERK signaling pathway, we show that the μ opioid agonist [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), acting via the endogenous μ opioid receptor (MOR), induced sequential epidermal growth factor receptor (EGF) receptor (EGFR) Tyr phosphorylation, Ser phosphorylation, and down-regulation in immortalized rat cortical astrocytes. The short-term action of DAMGO resulted in the stimulation of ERK phosphorylation. 4(3-Chlorophenylamino)-6,7-dimethoxyquinazoline (Tyrphostin AG1478), a selective inhibitor of EGFR Tyr kinase activity, blocked EGFR and ERK activation by short-term DAMGO administration, implicating EGFR transactivation in its stimulation of ERK activity. Inhibitors of matrix metalloproteinases attenuated MOR-mediated ERK phosphorylation, suggesting that shedding of EGF-like ligands from the plasma membrane may be involved in the EGFR transactivation process. Prolonged DAMGO exposure induced EGFR internalization/down-regulation, did not activate ERK, and inhibited exogenous EGF-stimulated ERK phosphorylation. MOR-mediated EGFR down-regulation seems to be MAP kinase-dependent, because it was inhibited by the ERK kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene (U0126), and tyrphostin AG1478. The κ opioid agonist (5α,7α,8β)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) induced Tyr and Ser phosphorylation of EGFR and activation of ERK. However, long-term application of U69,593 neither down-regulated EGFR nor inhibited EGF-induced ERK activation. Instead, it engendered a sustained activation of ERK. Collectively, our data suggest that long-term application of DAMGO initiates heterologous down-regulation of EGFR via a mechanism involving ERK in astrocytes.