G protein-mediated mitogen-activated protein kinase activation by two dopamine D2 receptors

Biochem Biophys Res Commun. 1999 Mar 5;256(1):33-40. doi: 10.1006/bbrc.1999.0286.


Two isoforms of dopamine D2 receptor, D2L (long) and D2S (short), differ by the insertion of 29 amino acids specific to D2L within the putative third intracellular loop of the receptor, which appears to be important in selectivity for G-protein coupling. We have generated D2L- and D2S-expressing Chinese hamster ovary (CHO) cells, and regulation of the mitogen-activated protein kinase (MAPK) pathway was examined in these cells. Both D2L and D2S mediated a rapid and transient activation of MAPK with dominant activation of p42-kDa MAPK. Pertussis toxin treatment completely abrogated stimulation of MAPK mediated by D2L and D2S, demonstrating that both receptors couple to pertussis toxin-sensitive G proteins in this signaling. Stimulation of MAPK mediated by both D2L and D2S receptor was markedly attenuated by coexpression of the C-terminus of beta-adrenergic receptor kinase (betaARKct), which selectively inhibits Gbetagamma-mediated signal transduction. Further analysis of D2L- and D2S-mediated MAPK activation demonstrated that D2L-mediated MAPK activation was not significantly affected by PKC depletion or partially affected by genistein. In contrast, D2S-mediated MAPK activation was potentially inhibited by PKC depletion and genistein was capable of completely inhibiting D2S-mediated MAPK activation. Together, these results suggest that D2L- and D2S-mediated MAPK activation is predominantly Gbetagamma subunit-mediated signaling and that protein kinase C and tyrosine phosphorylations are involved in these signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cricetinae
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dopamine / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dopamine D2 Receptor Antagonists
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Proteins / antagonists & inhibitors
  • GTP-Binding Proteins / metabolism*
  • Lysophospholipids / antagonists & inhibitors
  • Lysophospholipids / pharmacology
  • Mice
  • Peptide Fragments / metabolism
  • Pertussis Toxin
  • Phosphorylation / drug effects
  • Protein Isoforms / metabolism
  • Protein Kinase C / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Dopamine D2 / metabolism*
  • Signal Transduction* / drug effects
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transfection
  • Virulence Factors, Bordetella / pharmacology
  • beta-Adrenergic Receptor Kinases


  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Enzyme Inhibitors
  • Lysophospholipids
  • Peptide Fragments
  • Protein Isoforms
  • Receptors, Dopamine D2
  • Virulence Factors, Bordetella
  • Pertussis Toxin
  • Protein-Tyrosine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • beta-Adrenergic Receptor Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • GTP-Binding Proteins
  • Tetradecanoylphorbol Acetate
  • Dopamine