Phospholipase D2 modulates agonist-induced mu-opioid receptor desensitization and resensitization

J Neurochem. 2004 Feb;88(3):680-8. doi: 10.1046/j.1471-4159.2003.02189.x.


Receptor phosphorylation, arrestin binding, uncoupling from G protein and subsequent endocytosis have been implicated in G protein-coupled receptor desensitization after chronic agonist exposure. In search of proteins regulating the mu-opioid receptor endocytosis, we have recently established that activation of phospholipase D (PLD)2 is required for agonist-induced mu-opioid receptor endocytosis. In this study, we determined the effect of PLD2 activity on the desensitization and resensitization rate of the mu-opioid receptor. We clearly demonstrated that inhibition of PLD2-mediated phosphatidic acid formation by alcohol (1-butanol or ethanol) or overexpression of a dominant negative mutant of PLD2 prevented agonist-mediated endocytosis and resulted in a faster desensitization rate of the mu-opioid receptor after chronic (D-Ala2, Me Phe4, Glyol5)enkephalin treatment in human embryonic kidney 293 cells. Moreover, inhibition of PLD2 activity led to an impairment of the resensitization rate of the mu-opioid receptor. In summary, our data strongly suggest that PLD2 is a modulator of agonist-induced endocytosis, desensitization and resensitization of the mu-opioid receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Butanol / pharmacology
  • Analgesics, Opioid / pharmacology
  • Animals
  • Cell Line
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Humans
  • Phosphatidic Acids / antagonists & inhibitors
  • Phosphatidic Acids / biosynthesis
  • Phospholipase D / antagonists & inhibitors
  • Phospholipase D / physiology*
  • Protein Isoforms / agonists
  • Protein Isoforms / metabolism
  • Rats
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / metabolism*


  • Analgesics, Opioid
  • Phosphatidic Acids
  • Protein Isoforms
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • 1-Butanol
  • phospholipase D2
  • Phospholipase D