Phospholipase D2 modulates agonist‐induced µ‐opioid receptor desensitization and resensitization

Koch, Thomas; Brandenburg, Lars‐Ove; Liang, Ying-Jian; Schulz, Stefan; Beyer, Andréa; Schröder, Helmut; Höllt, Volker

doi:10.1046/j.1471-4159.2003.02189.x

Cited by 66 publications

(50 citation statements)

References 41 publications

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“…PLD2 has also been identified by yeast two-hybrid to associate with the -opioid receptor C-tail (Koch et al, 2003(Koch et al, , 2004. Our results establish a general role for PLD2 in the regulation of GPCR endocytosis.…”

Section: Discussionsupporting

confidence: 63%

“…Ral may also regulate EGF receptor endocytosis through its interaction with phospholipase D1 (PLD1) and PLD2 (Shen et al, 2001). However, a role for Ral in GPCR endocytosis has yet to be described, and it is not clear what functional role PLD2 plays in regulating clathrin-coated vesicle-mediated endocytosis (Shen et al, 2001;Koch et al, 2003Koch et al, , 2004Du et al, 2004). Here, we show that both Ral and PLD2 bind to class 1 mGluRs and act as proximal adaptor proteins, the activity of which is specifically required to promote constitutive mGluR endocytosis.…”

Section: Introductionmentioning

confidence: 79%

“…PLD2 is also activated by ARF proteins, but it is unclear whether Ral contributes to PLD2 regulation (Koch et al, 2003). PLD1 and PLD2 are associated with the EGF receptor, and PLD inhibitors block agonist-stimulated EGF, ␦-opioid, and angiotensin receptor internalization (Slaaby et al, 1998;Shen et al, 2001;Koch et al, 2003Koch et al, , 2004Du et al, 2004). Therefore, we examined whether the expression of wild-type and mutant ARF1, ARF6, PLD1, and PLD2 proteins might augment or antagonize constitutive mGluR1a internalization.…”

Section: Pld2 Regulates Constitutive Mglur Endocytosismentioning

confidence: 99%

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Ral and Phospholipase D2-Dependent Pathway for Constitutive Metabotropic Glutamate Receptor Endocytosis

Bhattacharya¹,

Babwah²,

Godin³

et al. 2004

J. Neurosci.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 79%

Section: Pld2 Regulates Constitutive Mglur Endocytosismentioning

confidence: 99%

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Ral and Phospholipase D2-Dependent Pathway for Constitutive Metabotropic Glutamate Receptor Endocytosis

Bhattacharya¹,

Babwah²,

Godin³

et al. 2004

J. Neurosci.

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“…It was shown previously that PLD2 was required for endocytosis of angiotensin receptor (33). Activity of PLD2 was also shown to be important for endocytosis, desensitization, and resensitization of -opioid receptor, and it was shown to directly interact with this receptor (34,35). It is shown here that both PLD1 and PLD2 were involved in sequestration of 5-HT 2A R. Because PLD1 and PLD2 have different cellular localization (33) it is possible that they control different steps of the observed sequestration.…”

Section: Discussionmentioning

confidence: 91%

Sustained Receptor Stimulation Leads to Sequestration of Recycling Endosomes in a Classical Protein Kinase C- and Phospholipase D-dependent Manner

Idkowiak‐Baldys¹,

Baldys

Raymond

et al. 2009

Journal of Biological Chemistry

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Considerable insight has been garnered on initial mechanisms of endocytosis of plasma membrane proteins and their subsequent trafficking through the endosomal compartment. It is also well established that ligand stimulation of many plasma membrane receptors leads to their internalization. However, stimulus-induced regulation of endosomal trafficking has not received much attention. In previous studies, we showed that sustained stimulation of protein kinase C (PKC) with phorbol esters led to sequestration of recycling endosomes in a juxtanuclear region. In this study, we investigated whether G-protein-coupled receptors that activate PKC exerted effects on endosomal trafficking. Stimulation of cells with serotonin (5-hydroxytryptamine (5-HT)) led to sequestration of the 5-HT receptor (5-HT 2A R) into a Rab11-positive juxtanuclear compartment. This sequestration coincided with translocation of PKC as shown by confocal microscopy. Mechanistically the observed sequestration of 5-HT 2A R was shown to require continuous PKC activity because it was inhibited by pretreatment with classical PKC inhibitor Gö6976 and could be reversed by posttreatment with this inhibitor. In addition, classical PKC autophosphorylation was necessary for receptor sequestration. Moreover inhibition of phospholipase D (PLD) activity and inhibition of PLD1 and PLD2 using dominant negative constructs also prevented this process. Functionally this sequestration did not affect receptor desensitization or resensitization as measured by intracellular calcium increase. However, the PKC-and PLD-dependent sequestration of receptors resulted in co-sequestration of other plasma membrane proteins and receptors as shown for epidermal growth factor receptor and protease activated receptor-1. This led to heterologous desensitization of those receptors and diverted their cellular fate by protecting them from agonist-induced degradation. Taken together, these results demonstrate a novel role for sustained receptor stimulation in regulation of intracellular trafficking, and this process requires sustained stimulation of PKC and PLD.

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“…M6a might also modulate the intracellular trafficking of certain other receptors since M6a interacts with a number of GPCRs [17]. It has been well documented that MOPr endocytosis reduces the development of opioid tolerance by promoting fast receptor resensitization and recycling [12,[40][41][42][43][44][45][46][47]. It is therefore reasonable to suggest that M6a-enhanced endocytosis/recycling of MOPrs attenuates the development of opiate tolerance.…”

Section: Discussionmentioning

confidence: 99%

Membrane glycoprotein M6A promotes μ-opioid receptor endocytosis and facilitates receptor sorting into the recycling pathway

Liang

Stumm

et al. 2008

Cell Res

Self Cite

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The interaction of μ-opioid receptor (MOPr) with the neuronal membrane glycoprotein M6a is known to facilitate MOPr endocytosis in human embryonic kidney 293 (HEK293) cells. To further study the role of M6a in the post-endocytotic sorting of MOPr, we investigated the agonist-induced co-internalization of MOPr and M6a and protein targeting after internalization in HEK293 cells that co-expressed HA-tagged MOPr and Myc-tagged M6a. We found that M6a, MOPr, and Rab 11, a marker for recycling endosomes, co-localized in endocytotic vesicles, indicating that MOPr and M6a are primarily targeted to recycling endosomes after endocytosis. Furthermore, co-expression of M6a augmented the post-endocytotic sorting of δ-opioid receptors into the recycling pathway, indicating that M6a might have a more general role in opioid receptor post-endocytotic sorting. The enhanced post-endocytotic sorting of MOPr into the recycling pathway was accompanied by a decrease in agonist-induced receptor down-regulation of M6a in co-expressing cells. We tested the physiological relevance of these findings in primary cultures of cortical neurons and found that co-expression of M6a markedly increased the translocation of MOPrs from the plasma membrane to intracellular vesicles at steady state and significantly enhanced both constitutive and agonist-induced receptor endocytosis. In conclusion, our results strongly indicate that M6a modulates MOPr endocytosis and post-endocytotic sorting and has an important role in receptor regulation.

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Phospholipase D2 modulates agonist‐induced µ‐opioid receptor desensitization and resensitization

Cited by 66 publications

References 41 publications

Ral and Phospholipase D2-Dependent Pathway for Constitutive Metabotropic Glutamate Receptor Endocytosis

Ral and Phospholipase D2-Dependent Pathway for Constitutive Metabotropic Glutamate Receptor Endocytosis

Sustained Receptor Stimulation Leads to Sequestration of Recycling Endosomes in a Classical Protein Kinase C- and Phospholipase D-dependent Manner

Membrane glycoprotein M6A promotes μ-opioid receptor endocytosis and facilitates receptor sorting into the recycling pathway

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