Arrestin-Dependent and -Independent Internalization of G Protein–Coupled Receptors: Methods, Mechanisms, and Implications on Cell Signaling

Agonist-induced endocytosis is a key regulatory mechanism for controlling the responsiveness of cell by changing density surface receptors. In addition to role in signal termination, endocytosed G protein–coupled receptors (GPCRs) have been found from intracellular compartments cell. Arrestins are generally believed be master regulators GPCR binding both phosphorylated and adaptor protein 2 (AP-2) or clathrin, thus recruiting clathrin-coated pits facilitate internalization process. However, many other functions described arrestins that do not relate their terminating signaling. Additionally, there now more than 30 examples GPCRs internalize independently arrestins. Here we review methods, pharmacological tools, cellular backgrounds used determine receptor internalization, highlighting advantages caveats. We also summarize arrestin-independent literature suggested alternative pathway (e.g., caveolae-dependent fast endophilin-mediated pathways). Finally, consider possible function recruited arrestins, including catalytic arrestin activation paradigm. Technological improvements recent years advanced field further, and, combined with important implications on drug responses, this makes an obvious parameter include molecular characterization ligand-GPCR interactions. SIGNIFICANCE STATEMENT (GPCR) means terminate signaling, play central widely accepted classical paradigm endocytosis. contrast canonical arrestin-mediated increasing number via alternate pathways, process appears diverse previously defined “one fits all.”