A Triple Arg Motif Mediates α _2B-Adrenergic Receptor Interaction with Sec24C/D and Export

Recent studies have demonstrated that cargo exit from the endoplasmic reticulum (ER) may be directed by ER export motifs recognized by components of the coat protein II (COPII) vesicles. However, little is known about ER export motifs and vesicle targeting of the G protein-coupled receptor (GPCR) superfamily. Here, we have demonstrated that a triple Arg (3R) motif in the third intracellular loop functions as a novel ER export signal for α _2B-adrenergic receptor (α _2B-AR). The 3R motif mediates α _2B-AR interaction with Sec24C/D and modulates ER exit, cell surface transport and function of α _2B-AR. Furthermore, export function of the 3R motif is independent of its position within α _2B-AR and can be conferred to CD8 glycoprotein. These data provide the first evidence implicating that export of GPCRs is controlled by code-directed interactions with selective components of the COPII transport machinery.