A transplantable sorting signal that is sufficient to mediate rapid recycling of G protein-coupled receptors

The beta (2)-adrenergic receptor and delta opioid receptor represent distin ct G protein-coupled receptors that undergo agonist-induced endocytosis via clathrin-coated pits but differ significantly in their postendocytic sorti ng between recycling and degradative membrane pathways, respectively. Previ ous results indicate that a distal portion of the carboxyl-terminal cytopla smic domain of the beta (2)-adrenergic receptor, which engages in PDZ domai n-mediated protein interaction, is required for efficient recycling of rece ptors after agonist-induced endocytosis. Here we demonstrate that a four-re sidue sequence (DSLL) comprising the core of this protein interaction domai n functions as a transplantable endocytic sorting signal that is sufficient to re-route endocytosed delta opioid receptor into a rapid recycling pathw ay, to inhibit proteolytic down-regulation of receptors, and to mediate rec eptor-autonomous sorting of mutant receptors from the wild type allele when co-expressed in the same cells. These observations define a transplantable signal mediating rapid recycling of a heterologous G protein-coupled recep tor, and they suggest that rapid recycling of certain membrane proteins doe s not occur by bulk membrane flow but is instead mediated by a specific end ocytic sorting mechanism.