Figure 2. Alternative Modes of GPCR Trafficking Along the Endocytic Network.

Upon ligand-induced activation GPCRs are internalized into early endosomes for sorting. At the early endosome, GPCRs containing C-terminal PDZ binding motifs are recognized by compatible PDZ-adaptor proteins such as SNX27, which works in conjunction with retromer and the WASH complex (Inset). Following sorting, receptors are packaged into recycling tubules which emanate and bud from the membranes of early endosomes. These recycling intermediaries transport GPCRs back to the plasma membrane leading to resensitization of the cell surface. Alternatively, GPCRs marked for degradation are sequestered into intraluminal vesicles (ILVs) of multivesicular endosomes that fuse with lysosomes resulting in receptor proteolysis and down-regulation at the cell surface. Membrane retrieval of endocytosed PTHR occurs via three divergent trafficking itineraries: (i) ASRT-mediated endosome-to-plasma membrane recycling (green); (ii) ASRT-independent endosome-to-PM recycling (blue) or (iii) retrograde endosome-to-TGN-PM recycling (red). This GPCR signaling-trafficking cycle is superimposed by the recruitment and functional transition of small Rab GTPases: early endosome (Rab5), late-endosome/lysosome (Rab7) and recycling endosomes (Rab4 and Rab11).