Prolonged exposure to a high ligand concentration induces GPCR desensitization to prevent receptor overstimulation. As the ligand-bound GPCR activates the G protein, G-alpha and G-beta gamma subunits dissociate. The free beta-gamma recruits GPCR kinase to the plasma membrane. Together, they phosphorylate activated GPCRs nearby. Phosphorylated GPCR tightly binds beta-arrestin, which blocks the binding of additional G proteins to the GPCR, thus inactivating the receptor. Beta-arrestin also facilitates clathrin assembly on the plasma membrane, which packages the beta-arrestin-GPCR complex in a vesicle and sequesters it in the endosome. The GPCR can be recycled back to the plasma membrane for another round of signaling. Alternatively, if the endosome fuses with a lysosome, the lysosomal enzymes degrade the GPCR, thus downregulating the receptors.