Phospholipase D2 modulates agonist-induced mu-opioid receptor desensitization and resensitization |
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Authors: | Koch Thomas Brandenburg Lars-Ove Liang Yingjian Schulz Stefan Beyer Andrea Schröder Helmut Höllt Volker |
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Institution: | Department of Pharmacology and Toxicology, Otto-von-Guericke University, Magdeburg, Germany. Thomas.Koch@Medizin.Uni-Magdeburg.de |
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Abstract: | 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. |
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Keywords: | desensitization endocytosis internalization µ-opioid receptor phospholipase D2 resensitization |
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