Regulation of Somatostatin receptor 2 trafficking by C-tail motifs and the retromer

The Gi-coupled somatostatin receptor 2 (SST2) is a G-protein coupled receptor (GPCR) that mediates many of somatostatin’s neuroendocrine actions. Upon stimulation, SST2 is rapidly internalized and transported to early endosomes before being recycled to the plasma membrane. However, little is known about the intracellular itinerary of SST2 after it moves to the early endosomal compartment, or the cytoplasmic proteins that regulate its trafficking. As Postsynaptic density protein/Discs large-1/Zona occludens-1 (PDZ) domain interactions often regulate the trafficking and signaling potential of other GPCRs, we examined the role of the SST2 PDZ ligand and additional C-terminal residues in controlling its intracellular trafficking. We determined that SST2 can recycle to the plasma membrane via multiple pathways, including a LAMP1/Rab7 positive late endosome to trans-Golgi network (TGN) pathway. Trafficking from the late endosome to the TGN is often regulated by the retromer complex of endosom...