Specific motifs mediate post-synaptic and surface transport of G protein-coupled receptors

G protein-coupled receptors (GPCRs) are key regulators of synaptic functions. However, their targeted trafficking to synapses after synthesis is poorly understood. Here, we demonstrate that multiple motifs mediate α_2B-adrenergic receptor transport to the dendritic and post-synaptic compartments in primary hippocampal neurons, with a single leucine residue on the first intracellular loop being specifically involved in synaptic targeting. The N-terminally located tyrosine-serine motif operates differently in neuronal and non-neuronal cells. We further show that the highly conserved dileucine (LL) motif in the C-terminus is required for the dendritic and post-synaptic traffic of all GPCRs studied. The LL motif also directs the export from the endoplasmic reticulum of a chimeric GPCR and confers its transport ability to vesicular stomatitis virus glycoprotein in cell lines. Collectively, these data reveal the intrinsic structural determinants for the synaptic targeting of nascent GPCRs and their cell-type-specific trafficking along the biosynthetic pathways.