Dopamine D2 receptor stimulation of mitogen-activated protein kinases mediated by cell type-dependent transactivation of receptor tyrosine kinases

J Neurochem. 2005 May;93(4):899-909. doi: 10.1111/j.1471-4159.2005.03055.x.


Dopamine D2 receptor activation of extracellular signal-regulated kinases (ERKs) in non-neuronal human embryonic kidney 293 cells was dependent on transactivation of the platelet-derived growth factor (PDGF) receptor, as demonstrated by the effect of the PDGF receptor inhibitors tyrphostin A9 and AG 370 on quinpirole-induced phosphorylation of ERKs and by quinpirole-induced tyrosine phosphorylation of the PDGF receptor. In contrast, ectopically expressed D2 receptor or endogenous D2-like receptor activation of ERKs in NS20Y neuroblastoma cells, which express little or no PDGF receptor, or in rat neostriatal neurons was largely dependent on transactivation of the epidermal growth factor (EGF) receptor, as demonstrated using the EGF receptor inhibitor AG 1478 and by quinpirole-induced phosphorylation of the EGF receptor. The D2 receptor agonist quinpirole enhanced the coprecipitation of D2 and EGF receptors in NS20Y cells, suggesting that D2 receptor activation induced the formation of a macromolecular signaling complex that includes both receptors. Transactivation of the EGF receptor also involved the activity of a matrix metalloproteinase. Thus, although D2 receptor stimulation of ERKs in both cell lines was decreased by inhibitors of ERK kinase, Src-family protein tyrosine kinases, and serine/threonine protein kinases, D2-like receptors activated ERKs via transactivation of the EGF receptor in NS20Y neuroblastoma cells and rat embryonic neostriatal neurons, but via transactivation of the PDGF receptor in 293 cells.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western / methods
  • Cells, Cultured
  • Dopamine Agonists / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation / physiology
  • Genetic Vectors / physiology
  • Humans
  • Indole Alkaloids / pharmacology
  • Microscopy, Confocal / methods
  • Neuroblastoma
  • Piperazines / pharmacology
  • Platelet-Derived Growth Factor / metabolism
  • Quinazolines
  • Quinpirole / pharmacology
  • Radioligand Assay / methods
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism*
  • Simplexvirus / physiology
  • Spiperone / pharmacology
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology*
  • Transfection / methods
  • Tritium / pharmacology
  • Tyrphostins / pharmacology


  • Dopamine Agonists
  • Dopamine Antagonists
  • Enzyme Inhibitors
  • Indole Alkaloids
  • Piperazines
  • Platelet-Derived Growth Factor
  • Quinazolines
  • Receptors, Dopamine D2
  • Tyrphostins
  • tryprostatin A
  • Tritium
  • RTKI cpd
  • Quinpirole
  • Spiperone
  • Epidermal Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Extracellular Signal-Regulated MAP Kinases