Analysis of Chemokine Receptor Endocytosis and Recycling

Endocytosis regulates the cell-surface expression of many seven transmembrane G-protein coupled receptors (7 TM-GPCRs) and has been implicated in both desensitization following agonist-induced activation and resensitization (1 ,2 ). The internalization mechanism for many 7 TM-GPCRs has not been clearly established. However, a clear paradigm is emerging for the β₂ -adrenergic receptor (β₂ AR) (1 ,2 ). For β₂ AR, agonist binding induces activation of heterotrimeric G proteins, which in turn activate one or more members of the family of G-protein coupled receptor kinases (GRKs). GRK-mediated phosphorylation of the receptor enhances the binding of β-arrestins, proteins that uncouple heterotrimeric G protein activation and link the receptor to clathrincoated pits by binding to clathrin heavy chains (1 –3 ). Coated vesicles internalize the receptors and deliver them to endosomes, where they can be dephosphorylated and recycled to the cell surface (4 ).