Fig. 1. Role of ß-arrestins in the desensitization, sequestration and intracellular trafficking of GPCRs. Homologous desensitization of GPCRs (1) results from the binding of ß-arrestins (ß-arr) to agonist (H)-occupied receptors following phosphorylation of the receptor by GRKs. ß-arrestin binding sterically precludes coupling between the receptor and heterotrimeric G proteins, leading to termination of signaling by G proteins effectors (E). Receptor-bound ß-arrestins also act as adapter proteins, binding to components of the clathrin endocytic machinery including clathrin, ß2-adaptin (AP-2) and NSF. Receptor sequestration (2) reflects the dynamin (Dyn)-dependent endocytosis of GPCRs via clathrin-coated pits. Once internalized, GPCRs exhibit two distinct patterns of ß-arrestin interaction. `Class A' GPCRs, for example the ß2 adrenergic receptor, rapidly dissociate from ß-arrestin upon internalization. These receptors are trafficked to an acidified endosomal compartment, wherein the ligand is dissociated and the receptor dephosphorylated by a GPCR-specific protein phosphatase PP2A isoform, and are subsequently recycled to the plasma membrane (3). `Class B' receptors, for example the angiotensin II AT1a receptor, form stable receptor-ß-arrestin complexes. These receptors accumulate in endocytic vesicles and are either targeted for degradation or slowly recycled to the membrane via as yet poorly defined routes.

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