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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 beta sub 2 -adrenergic receptor (beta2 AR). beta sub 2 AR signalling is rapidly attenuated through receptor phosphorylation and subsequent binding of the protein beta-arrestin [1,2]. Ultimately the receptor undergoes internalization [3,4], and although the molecular mechanism is unclear, receptor phosphorylation and beta-arrestin binding have been implicated in this process [5,6]. Here we report that beta-arrestin and arrestin-3, but not visual arrestin, promote beta2 AR internalization and bind with high affinity directly and stoichiometrically to clathrin, the major structural protein of coated pits. Moreover, beta-arrestin/arrestin chimaeras that are defective in either beta2 AR or clathrin binding show a reduced ability to promote beta2 AR endocytosis. Immunofluorescence microscopy of intact cells indicates an agonist-dependent colocalization of the beta2 AR and beta-arrestin with clathrin. These results show that beta-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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