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β-Arrestin acts as a clathrin adaptor in endocytosis of the β2-adrenergic receptor


THE ability of a system to regulate its responsiveness in the presence of a continuous stimulus, often termed desensitization, has been extensively characterized for the β2-adrenergic receptor (β2AR). β2AR signalling is rapidly attenuated through receptor phosphorylation and subsequent binding of the protein β-arrestin1,2. Ultimately the receptor undergoes internalization3,4, and although the molecular mechanism is unclear, receptor phosphorylation and β-arrestin binding have been implicated in this process5,6. Here we report that p-arrestin and arrestin-3, but not visual arrestin, promote β2AR internalization and bind with high affinity directly and stoichiometrically to clathrin, the major structural protein of coated pits. Moreover, β-arrestin/arrestin chimaeras that are defective in either β2AR or clathrin binding show a reduced ability to promote β2AR endocytosis. Immunofluorescence microscopy of intact cells indicates an agonist-dependent colocalization of the β2AR and β-arrestin with clathrin. These results show that β-arrestin functions as an adaptor in the receptor-mediated endocytosis pathway, and suggest a general mechanism for regulating the trafficking of G-protein-coupled receptors.

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Goodman, O., Krupnick, J., Santini, F. et al. β-Arrestin acts as a clathrin adaptor in endocytosis of the β2-adrenergic receptor. Nature 383, 447–450 (1996).

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