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Opioid control of MAP kinase cascade

Rüdiger Schulz1, Daniela A Eisinger, Andrea Wehmeyer

  • 1Institute of Pharmacology, Toxicology and Pharmacy, University of Munich, Königinstr. 16, D-80539 München, Germany. schulz@pharmtox.vetmed.uni-muenchen.de

European Journal of Pharmacology
|October 7, 2004
PubMed

Insights

Opioid receptor activation stimulates mitogen-activated protein kinase (MAPK) cascade via epidermal growth factor (EGF) receptor signaling. Different opioid receptors activate ERK 1/2 differently, suggesting distinct EGF receptor involvement.

Area of Science:

  • Cellular signaling pathways
  • Molecular pharmacology
  • Neuroscience

Background:

  • G protein-coupled receptors (GPCRs) activation can lead to extracellular signal-regulated kinases 1/2 (ERK 1/2) phosphorylation.
  • This signaling often involves ectodomain shedding, producing epidermal growth factor (EGF)-like ligands that activate mitogen-activated protein kinase (MAPK) pathways via EGF receptors.

Purpose of the Study:

  • To investigate the control of MAPK pathways by opioidergic GPCRs in human embryonic kidney (HEK 293) cells.
  • To elucidate the specific EGF receptor subtypes involved in ERK activation downstream of opioid receptor stimulation.

Main Methods:

  • Experiments utilized HEK 293 cells engineered to express opioid receptors, G protein-coupled receptor kinases, and ERKs.
  • Investigated receptor internalization and ERK phosphorylation in response to EGF and opioid receptor agonists.

Main Results:

  • Opioid receptor stimulation releases EGF-like ligands that activate ERK 1/2 through distinct EGF receptors, differing from EGF's direct activation via EGF receptor type 1.
  • Mu-, delta-, and kappa-opioid receptors exhibit differential activation of ERKs.
  • EGF rapidly internalizes EGF receptor type 1, whereas opioid receptor stimulation does not induce similar sequestration, indicating engagement of alternative EGF receptor types.

Conclusions:

  • Opioidergic GPCRs modulate the MAPK cascade similarly to other GPCRs, with notable distinctions among mu, delta, and kappa receptor subtypes.
  • EGF-induced ERK activation is mediated by EGF receptor type 1, while opioid receptor activation appears to involve a different EGF receptor type.

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