Dimerization of the delta opioid receptor: implication for a role in receptor internalization.

Dimerization of G-protein-coupled receptors has been increasingly noted in the regulation of their biological activity. However, its involvement in agonist-induced receptor internalization is not well understood. In this study, we examined the ability of mouse delta-opioid receptors to dimerize and the role of receptor dimerization in agonist-induced internalization. Using differentially (Flag and c-Myc) epitope-tagged receptors we show that delta-opioid receptors exist as dimers. The level of dimerization is agonist dependent. Increasing concentrations of agonists reduce the levels of dimer with a corresponding increase in the levels of monomer. Interestingly, morphine does not affect the levels of either form. It has been shown that morphine, unlike other opioid agonists, does not induce receptor internalization. This suggests a relationship between the ability of agonists to reduce the levels of dimer and to induce receptor internalization. The time course of the agonist-induced decrease of delta-opioid receptor dimers is shorter than the time course of internalization, suggesting that monomerization precedes the agonist-induced internalization of the receptor. Furthermore, we found that a mutant delta-opioid receptor, with a 15-residue C-terminal deletion, does not exhibit dimerization. This mutant receptor has been shown to lack the ability to undergo agonist-induced internalization. These results suggest that the interconversion between the dimeric and monomeric forms plays a role in opioid receptor internalization.