Phospholipase D2 modulates agonist-induced mu-opioid receptor desensitization and resensitization.
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.
Koch
Thomas
T
Department of Pharmacology and Toxicology, Otto-von-Guericke University, Magdeburg, Germany. Thomas.Koch@Medizin.Uni-Magdeburg.de
Brandenburg
Lars-Ove
LO
Liang
Yingjian
Y
Schulz
Stefan
S
Beyer
Andrea
A
Schröder
Helmut
H
Höllt
Volker
V
D020001:1-Butanol / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006801:Humans; D010712:Phosphatidic Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000502:physiology*; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism*
D000701:Analgesics, Opioid; D010712:Phosphatidic Acids; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020001:1-Butanol; C105606:phospholipase D2; D010739:Phospholipase D