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First published online 20 January 2004
doi: 10.1242/jcs.00878

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Differences in endosomal targeting of human ß₁- and ß₂-adrenergic receptors following clathrin-mediated endocytosis

Membrane Biochemistry Section, Laboratory of Molecular and Cellular Neurobiology, National Institute of Neurological Disorders and Stroke, The National Institutes of Health, Bethesda, MD 20892, USA

^* Author for correspondence (e-mail: fishmanp{at}ninds.nih.gov)

Accepted 17 September 2003

The ß₂-adrenergic receptor (ß₂AR) undergoes agonist-mediated endocytosis via clathrin-coated pits by a process dependent on both arrestins and dynamin. Internalization of some G protein-coupled receptors, however, is independent of arrestins and/or dynamin and through other membrane microdomains such as caveolae or lipid rafts. The human ß₁AR is less susceptible to agonist-mediated internalization than the ß₂-subtype, and its endocytic route, which is unknown, may be different. We have found that (i) co-expression of arrestin-2 or -3 enhanced the internalization of both subtypes whereas co-expression of dominant-negative mutants of arrestin-2 or dynamin impaired their internalization, as did inhibitors of clathrin-mediated endocytosis. (ii) Agonist stimulation increased the phosphorylation of ß₂AR but not ß₁AR. (iii) In response to agonist, each subtype redistributed from the cell surface to a distinct population of cytoplasmic vesicles; those containing ß₁AR were smaller and closer to the plasma membrane whereas those containing ß₂AR were larger and more perinuclear. (iv) When subcellular fractions from agonist-treated cells were separated by sucrose density gradient centrifugation, all of the internalized ß₂AR appeared in the lighter endosomal-containing fractions whereas some of the internalized ß₁AR remained in the denser plasma membrane-containing fractions. (v) Both subtypes recycled with similar kinetics back to the cell surface upon removal of agonist; however, recycling of ß₂AR but not ß₁AR was inhibited by monensin. Based on these results, we propose that the internalization of ß₁AR is both arrestin- and dynamin-dependent and follows the same clathrin-mediated endocytic pathway as ß₂AR. But during or after endocytosis, ß₁AR and ß₂AR are sorted into different endosomal compartments.

Key words: ß-Adrenergic receptor, Endocytosis, Recycling, Clathrin, Arrestin

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