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Molecular Pharmacology

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Research ArticleArticle

μ Opioid Transactivation and Down-Regulation of the Epidermal Growth Factor Receptor in Astrocytes: Implications for Mitogen-Activated Protein Kinase Signaling

Mariana M. Belcheva, Yun Tan, Virginia M. Heaton, Amy L. Clark and Carmine J. Coscia
Molecular Pharmacology December 2003, 64 (6) 1391-1401; DOI: https://doi.org/10.1124/mol.64.6.1391
Mariana M. Belcheva
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Yun Tan
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Virginia M. Heaton
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Amy L. Clark
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Carmine J. Coscia
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Abstract

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.

  • Received March 7, 2003.
  • Accepted September 2, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (6)
Molecular Pharmacology
Vol. 64, Issue 6
1 Dec 2003
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Research ArticleArticle

μ Opioid Transactivation and Down-Regulation of the Epidermal Growth Factor Receptor in Astrocytes: Implications for Mitogen-Activated Protein Kinase Signaling

Mariana M. Belcheva, Yun Tan, Virginia M. Heaton, Amy L. Clark and Carmine J. Coscia
Molecular Pharmacology December 1, 2003, 64 (6) 1391-1401; DOI: https://doi.org/10.1124/mol.64.6.1391

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Research ArticleArticle

μ Opioid Transactivation and Down-Regulation of the Epidermal Growth Factor Receptor in Astrocytes: Implications for Mitogen-Activated Protein Kinase Signaling

Mariana M. Belcheva, Yun Tan, Virginia M. Heaton, Amy L. Clark and Carmine J. Coscia
Molecular Pharmacology December 1, 2003, 64 (6) 1391-1401; DOI: https://doi.org/10.1124/mol.64.6.1391
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