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 α2B-adrenergic receptor (α2B-AR). The 3R motif mediates α2B-AR interaction with Sec24C/D and modulates ER exit, cell surface transport and function of α2B-AR. Furthermore, export function of the 3R motif is independent of its position within α2B-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.