Opioid modulation of extracellular signal-regulated protein kinase activity is ras-dependent and involves Gbetagamma subunits

J Neurochem. 1998 Feb;70(2):635-45. doi: 10.1046/j.1471-4159.1998.70020635.x.


Although it is well-established that G protein-coupled receptor signaling systems can network with those of tyrosine kinase receptors by several mechanisms, the point(s) of convergence of the two pathways remains largely undelineated, particularly for opioids. Here we demonstrate that opioid agonists modulate the activity of the extracellular signal-regulated protein kinase (ERK) in African green monkey kidney COS-7 cells transiently cotransfected with mu-, delta-, or kappa-opioid receptors and ERK1- or ERK2-containing plasmids. Recombinant proteins in transfected cells were characterized by binding assay or immunoblotting. On treatment with corresponding mu- ([D-Ala2,Me-Phe4,Gly-ol5]enkephalin)-, delta- ([D-Pen2,D-Pen5]enkephalin)-, or kappa- (U69593)-selective opioid agonists, a dose-dependent, rapid stimulation of ERK1 and ERK2 activity was observed. This activation was inhibited by specific antagonists, suggesting the involvement of opioid receptors. Pretreatment of cells with pertussis toxin abolished ERK1 and ERK2 activation by agonists. Cotransfection of cells with dominant negative mutant N17-Ras or with a betagamma scavenger, CD8- beta-adrenergic receptor kinase-C, suppressed opioid stimulation of ERK1 and ERK2. When epidermal growth factor was used to activate ERK1, chronic (>2-h) opioid agonist treatment resulted in attenuation of the stimulation by the growth factor. This inhibition was blocked by the corresponding antagonists and CD8- beta-adrenergic receptor kinase-C cotransfection. These results suggest a mechanism involving Ras and betagamma subunits of Gi/o proteins in opioid agonist activation of ERK1 and ERK2, as well as opioid modulation of epidermal growth factor-induced ERK activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzeneacetamides*
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Chlorocebus aethiops
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalin, D-Penicillamine (2,5)-
  • Enkephalins / pharmacology
  • Epidermal Growth Factor / pharmacology
  • GTP-Binding Proteins / metabolism*
  • Kinetics
  • Macromolecular Substances
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Pertussis Toxin
  • Pyrrolidines / pharmacology
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / biosynthesis
  • Receptors, Opioid, delta / physiology*
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / biosynthesis
  • Receptors, Opioid, kappa / physiology*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / biosynthesis
  • Receptors, Opioid, mu / physiology*
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transfection
  • Virulence Factors, Bordetella / pharmacology
  • ras Proteins / biosynthesis*


  • Benzeneacetamides
  • Enkephalins
  • Macromolecular Substances
  • Pyrrolidines
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Recombinant Proteins
  • Virulence Factors, Bordetella
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Epidermal Growth Factor
  • Enkephalin, D-Penicillamine (2,5)-
  • Pertussis Toxin
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins
  • ras Proteins
  • U 69593