Divers pathways mediate δ-opioid receptor down regulation within the same cell

Ma'anit Shapira, Ora Keren, Mikhal Gafni, Yosef Sarne*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Various mechanisms have been proposed for opioid receptor down regulation in different experimental preparations. The present study was aimed to test whether distinct mechanisms can mediate opioid receptor down regulation within the same cell. For this purpose we transfected HEK-293 cells with rat δ-opioid receptor (DOR). We exposed the cells to the opioid agonist etorphine in the absence or presence of various pharmacological agents and measured the binding of the opioid ligand [3H]diprenorphine to either isolated cell membranes or whole cells. We found that internalization of the receptors into the cell was mediated by clathrin coated pits and that the internalized receptors were degraded either in lysosomes or by proteosomes. Down regulation involved phosphorylation and at least two different kinases, a tyrosine kinase (TK) and MAPK kinase (MEK), mediated DOR down regulation in parallel routes. G-protein-coupled receptor kinase (GRK) was found to have only a minor role in DOR down regulation in HEK-293 cells. On the other hand, in N18TG2 cells that endogenously express δ-opioid receptors, GRK was the predominant kinase mediating DOR down regulation, with only a minor role for TK and MEK. We conclude that down regulation can take place via divers pathways within the same cell, and that in different cells down regulation is mediated by different mechanisms, depending on the kinase profile of the cells and the compartmentalization of the receptors within the cells.

Original languageEnglish
Pages (from-to)142-150
Number of pages9
JournalMolecular Brain Research
Issue number1-2
StatePublished - 30 Nov 2001


FundersFunder number
Israel Academy of Sciences and Humanities184-99
Israel Science Foundation


    • G-protein-coupled receptor
    • Opioid receptors
    • Phosphorylation
    • Receptor down regulation
    • Receptor internalization


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