Regulation of anterograde transport of α₂-adrenergic receptors by the N termini at multiple intracellular compartments

The studies on the intrinsic structural determinants for export trafficking of G protein-coupled receptors (GPCRs) have been mainly focused on the C termini of the receptors. In this report we determined the role of the extracellular N termini of α₂-adrenergic receptors (α₂-ARs) in the anterograde transport from the endoplasmic reticulum (ER) through the Golgi to the cell surface. The N-terminal-truncated α_2B-AR mutant is completely unable to target to the cell surface. A single Met-6 residue is essential for the export of α_2B-AR from the ER, likely through modulating correct α_2B-AR folding in the ER. The Tyr-Ser motif, highly conserved in the membrane-proximal N termini of all α₂-AR subtypes, is required for the exit of α_2A-AR and α_2B-AR from the Golgi apparatus, thus representing a novel Tyr-based motif modulating GPCR transport at the Golgi level. These data provide the first evidence indicating an essential role of the N termini of GPCRs in the export from distinct intracellular compartments along the secretory pathway.