Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors
Article first published online: 15 MAR 2006
Journal of Neurochemistry
Volume 97, Issue 2, pages 365–372, April 2006
How to Cite
Koch, T., Wu, D.-F., Yang, L.-Q., Brandenburg, L.-O. and Höllt, V. (2006), Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors. Journal of Neurochemistry, 97: 365–372. doi: 10.1111/j.1471-4159.2006.03736.x
- Issue published online: 15 MAR 2006
- Article first published online: 15 MAR 2006
- Received November 1, 2005; revised manuscript received December 1, 2005; accepted January 3, 2006.
- cannabinoid receptor 1;
- δ-opioid receptor;
- µ-opioid receptor;
- phospholipase D2
We have recently shown that the μ-opioid receptor [MOR1, also termed μ-opioid peptide (MOP) receptor] is associated with the phospholipase D2 (PLD2), a phospholipid-specific phosphodiesterase located in the plasma membrane. We further demonstrated that, in human embryonic kidney (HEK) 293 cells co-expressing MOR1 and PLD2, treatment with (D-Ala2, Me Phe4, Glyol5)enkephalin (DAMGO) led to an increase in PLD2 activity and an induction of receptor endocytosis, whereas morphine, which does not induce opioid receptor endocytosis, failed to activate PLD2. In contrast, a C-terminal splice variant of the μ-opioid receptor (MOR1D, also termed MOP1D) exhibited robust endocytosis in response to both DAMGO and morphine treatment. We report here that MOR1D also mediates an agonist-independent (constitutive) PLD2-activation facilitating agonist-induced and constitutive receptor endocytosis. Inhibition of PLD2 activity by over-expression of a dominant negative PLD2 (nPLD2) blocked the constitutive PLD2 activation and impaired the endocytosis of MOR1D receptors. Moreover, we provide evidence that the endocytotic trafficking of the δ-opioid receptor [DOR, also termed δ-opioid peptide (DOP) receptor] and cannabinoid receptor isoform 1 (CB1) is also mediated by a PLD2-dependent pathway. These data indicate the generally important role for PLD2 in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor (GPCR) endocytosis.