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J Pharmacol Exp Ther. 2002 Feb;300(2):376-84.

Opioid receptor types selectively cointernalize with G protein-coupled receptor kinases 2 and 3.

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  • 1Institute of Pharmacology, Toxicology and Pharmacy, University of Munich, München, Germany.


Activation of G protein-coupled receptors (GPCRs) may bring about their disappearance from the cell membrane, and it is commonly accepted that G protein-coupled receptor kinases (GRKs) play a key function in this mechanism. Opioid receptors belong to the family of GPCRs and are substrates of GRKs. We examined the fate of delta- and mu-opioid receptors and GRK2 and 3 in living cells during the process of receptor sequestration, using laser scanning microscopy. For visualization purposes, receptors and kinases were tagged at their respective C terminus with a fluorophore. The opioid receptors were fused to enhanced green fluorescence protein (EGFP), and the GRKs were linked to red fluorescence protein (DsRed). The cDNAs of these constructs served for transfection of human embryonic kidney 293 cells and neuroblastoma-glioma hybrid cells (NG 108-15), respectively. We report that activation of delta-opioid-EGFP receptors triggers a rapid translocation of cytosolic GRK-DsRed toward the cell membrane, which in turn releases vesicles carrying both green fluorescent delta-receptors and red fluorescent GRKs. Phosducin, a Gbetagamma scavenger, completely prevents translocation of GRKs and the formation of vesicles. In analogous experiments with mu-opioid receptors fused to EGFP, we observed that receptor activation also discharges green fluorescent vesicles. In contrast to delta-receptors, mu-receptors failed to trigger accumulation of GRK2 or 3 at the membrane, and no cointernalization of mu-opioid receptors with GRK2 or 3 was observed. The results suggest that delta-opioid receptors, but not mu-receptors, cointernalize with GRK2 or 3.

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