Abstract
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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References
Sterne-Marr, R. & Benovic, J. L. Vitam. Horm. 51, 193–234 (1995).
Premont, R. T., Inglese, J. & Lefkowitz, R. J. FASEB J. 9, 175–182 (1995).
Yu, S. S., Lefkowitz, R. J. & Hausdorff, W. P. J. Biol. Chem. 268, 337–341 (1993).
Pippig, S., Andexinger, S. & Lohse, M. J. Mol. Pharmacol. 47, 666–676 (1995).
Ferguson, S. S. G. et al. J. Biol. Chem. 270, 24782–24789 (1995).
Ferguson, S. S. G. et al. Science 271, 363–365 (1996).
von Zastrow, M. & Kobilka, B. K. J. Biol. Chem. 269, 18448–18452 (1994).
Sterne-Marr, R. et al. J. Biol. Chem. 268, 15640–15648 (1993).
Schroder, S. & Ungewickell, E. J. Biol. Chem. 266, 7910–7918 (1991).
Peeler, J. S., Donzell, W. C. & Anderson, R. G. W. J. Cell Biol. 120, 47–54 (1993).
Schmid, S. L. & Rothman, J. E. J. Biol. Chem. 260, 10044–10049 (1985).
Gurevich, V. V. et al. J. Biol. Chem. 270, 720–731 (1995).
Keen, J. H. Annu. Rev. Biochem. 59, 415–438 (1990).
Pearse, B. M. F. & Bretscher, M. S. Annu. Rev. Biochem. 50, 85–101 (1981).
Pearse, B. M. F. EMBO J. 7, 3331–3336 (1988).
Sorkin, A. & Carpenter, G. Science 261, 612–615 (1993).
Nesterov, A., Wiley, H. S. & Gill, G. N. Proc. Natl Acad. Sci. USA 92, 8719–8723 (1995).
Sorkin, A., Mazzotti, M., Sorkin, T., Scotto, L. & Beguinot, L. J. Biol. Chem. 271, 13377–13384 (1996).
Santini, F. & Keen, J. H. J. Cell Biol. 132, 1025–1036 (1996).
Freedman, N. J. et al. J. Biol. Chem. 270, 17953–17961 (1995).
Diviani, D. et al. J. Biol. Chem. 271, 5049–5058 (1996).
Gurevich, V. V. & Benovic, J. L. J. Biol. Chem. 267, 21919–21923 (1992).
Keen, J. H., Willingham, M. C. & Pastan, I. H. Cell 16, 303–312 (1979).
Goodman, O. B. & Keen, J. H. J. Biol. Chem. 270, 23768–23773 (1995).
Shinohara, T. et al. Proc. Natl Acad. Sci. USA 84, 6975–6979 (1987).
Lohse, M. J., Benovic, J. L., Codina, J., Caron, M. G. & Lefkowitz, R. J. Science 248, 1547–1550 (1990).
Dua, H. S. et al. Curr. Eye Res. 11 (suppl.), 107–111 (1992).
Keen, J. H., Willingham, M. C. & Pastan, I. J. Cell Biol. 256, 2538–2544 (1981).
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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). https://doi.org/10.1038/383447a0
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DOI: https://doi.org/10.1038/383447a0
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