A novel endocytic recycling signal that distinguishes the membrane trafficking of naturally occurring opioid receptors

delta and mu opioid receptors are homologous G protein-coupled receptors that are differentially sorted between divergent degradative and recycling membrane pathways following agonist-induced endocytosis. Whereas delta opioid receptors are selectively sorted to lysosomes, mu opioid receptors recycle rapidly to the plasma membrane by a process that has been proposed to occur via bulk membrane flow. We have observed that mu opioid receptors do not recycle by default and have defined a specific sequence present in the cytoplasmic tail of the cloned mu opioid receptor that is both necessary and sufficient for rapid recycling of internalized receptors. This sequence is completely distinct from a sequence shown previously to be required for recycling of the beta(2) adrenergic receptor yet is functionally interchangeable when tested in chimeric mutant receptors. These results indicate that signal-dependent recycling is a more common property of G protein-coupled receptors than previously appreciated and demonstrate that such a modular recycling signal distinguishes the regulation of homologous receptors that are naturally co-expressed.