Agonist-induced long-term desensitization of the human prostacyclin receptor

FEBS Lett. 2000 Nov 10;484(3):211-6. doi: 10.1016/s0014-5793(00)02156-6.


Phosphorylation of the human prostacyclin (PGI(2)) receptor (hIP-R) by diacylglycerol-regulated protein kinase C (PKC) has been reported to be responsible for its rapid desensitization in HEK293 cells. In this study we demonstrate, that human fibroblasts reveal a much slower hIP-R desensitization kinetics, which was neither affected by stimulation nor inhibition of PKC by either phorbol 12-myristate-13-acetate or GF-109203X suggesting a different cellular mechanism. Although agonist-promoted sequestration of a C-terminally green fluorescent protein-tagged hIP-R was demonstrated, it did not account for the long-term desensitization. Concanavalin A did not abolish, but accelerated receptor desensitization kinetics. Resensitization of hIP-R involved receptor recycling and/or de novo synthesis of receptor protein, depending on the duration of prior desensitization. This is the first study investigating the mechanisms of hIP-R desensitization in intact human cells naturally expressing hIP-R. Our data suggest, that a hitherto unknown mechanism of hIP-R long-term desensitization, which is independent of receptor phosphorylation by conventional and novel type PKC isoforms or endocytosis, is a key event in regulating the cellular responsiveness to PGI(2).

MeSH terms

  • Cell Line
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • G-Protein-Coupled Receptor Kinase 5
  • Humans
  • Iloprost / pharmacology*
  • Indoles / pharmacology
  • Kinetics
  • Maleimides / pharmacology
  • Phosphorylation
  • Polymerase Chain Reaction
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin / drug effects
  • Receptors, Prostaglandin / genetics
  • Receptors, Prostaglandin / physiology*
  • Recombinant Fusion Proteins / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transfection
  • beta-Adrenergic Receptor Kinases


  • Indoles
  • Maleimides
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin
  • Recombinant Fusion Proteins
  • Cyclic AMP
  • Protein Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 5
  • GRK5 protein, human
  • Iloprost
  • bisindolylmaleimide I
  • Tetradecanoylphorbol Acetate