Arrestin-mediated trafficking and compartmentalized biology of GPCRs

For many years, the primary function of arrestins was believed to be a master regulator of desensitization of G protein-coupled receptors (GPCRs) by the following mechanism. Upon activation and initiation of signaling, GPCRs are phosphorylated by GPCR kinases (GRKs) and/or protein kinase A/C at serine/threonine residues in either their C-terminal tail or the third intracellular loop. Phosphorylation of these serine/threonine sites is sensed by arrestins, which translocate from the cytoplasm to the phosphorylated receptor at the cell surface. Arrestins interact with the phosphorylated receptor residues via positively charged arginine and lysine residues that line the surface of the arrestin N-terminal lobe, which leads to significant structural changes within arrestins. These changes include rotation of the N- and C-terminal lobes relative to one another, a major reorientation of the “lariat loop” implicated in maintaining the inactive state of arrestin, and an outwards extension of the finger loop (FL). The extended arrestin FL binds to the transmembrane receptor core where it partially blocks the G protein-binding site and thereby uncouples G proteins from the receptors. This uncoupling of G proteins is considered a major mechanism underlying arrestin-mediated desensitization of GPCR signaling. A second desensitization mechanism that involves arrestins is receptor endocytosis where GPCRs are removed from the cell surface, and are thus no longer accessible to activating ligands in the extracellular environment. Once receptors have been internalized, they are either trafficked to lysosomes for degradation or recycled back to the plasma membrane for resensitization. This sorting process is critical as it determines whether the GPCR is destined for lysosomal destruction or whether it will get resensitized and ready for another round of activation at the cell surface.