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Relationship between Ser363 phosphorylation and internalization of the delta opioid receptor

Phosphorylation of Ser363 in the cytoplasmic tail of the delta opioid receptor (DOR) usually precedes receptor internalization, but is not necessarily a prerequisite for internalization. In these studies we measured phosphorylation of DOR Ser363 and DOR internalization in HEK 293 cells stably expressing FLAG‐tagged DOR in response to exposure to a variety of agonists. These agonist‐mediated responses were compared with their efficacy in the [35S]GTPγS assay. The agonists DPDPE and deltorphin were fully efficacious in the [35S]GTPγS assay and produced extensive phosphorylation and internalization. Morphine was a partial agonist in the [35S]GTPγS assay and failed to induce phosphorylation or internalization. In contrast, TAN‐67 a putative DOR1 agonist with a high degree of efficacy in the [35S]GTPγS assay, caused a high degree of Ser363 phosphorylation but very little internalization. A further disconnect between Ser363 phosphorylation and internalization was observed in FLAG‐tagged DOR cells where overexpression of GRK 2, 5, or 6 increased morphine‐induced phosphorylation of DOR Ser363, but did not increase morphine‐induced internalization. Conversely, overexpression of dominant negative GRK2‐K220R decreased DPDPE‐induced internalization. These results confirm a disconnection between phosphorylation of Ser363 and internalization. Supported by DA04087 and DA07261.