DELTA-OPIOID AND KAPPA-OPIOID RECEPTORS ARE DIFFERENTIALLY REGULATED BY DYNAMIN-DEPENDENT ENDOCYTOSIS WHEN ACTIVATED BY THE SAME ALKALOID AGONIST

Many alkaloid drugs used as analgesics activate multiple opioid recept ors. Mechanisms that distinguish the actions of these drugs on the reg ulation of individual mu, delta, and kappa receptors are not understoo d. We have observed that individual cloned opioid receptors differ Sig nificantly in their regulation by rapid endocytosis in the presence of alkaloid drug etorphine, a potent agonist of mu, delta, and kappa opi oid receptors. Internalization of epitope-tagged delta opioid receptor s from the plasma membrane is detectable within 10 min in the presence of etorphine. In contrast, kappa receptors expressed in the same cell s remain in the plasma membrane and are not internalized for greater t han or equal to 60 min, even when cells are exposed to saturating conc entrations of etorphine. The rapid internalization of delta receptors is specifically inhibited in cells expressing K44E mutant dynamin I, s uggesting that type-specific internalization of opioid receptors is me diated by clathrin-coated pits. Examination of a series of chimeric mu tant kappa/delta receptors indicates that at least two receptor domain s, including the highly divergent carboxyl-termindi cytoplasmic tail, determine the type specificity of this endocytic mechanism. We conclud e that structurally homologous opioid receptors are differentially sor ted by clathrin-mediated endocytosis following-activation by the same agonist ligand. These studies identify a fundamental mechanism of rece ptor regulation mediating type-specific effects of analgesic drugs tha t activate more than one type of opioid receptor.