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First published online 6 January 2004
doi: 10.1242/jcs.00890

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Trafficking of ß₂-adrenergic receptors: insulin and ß-agonists regulate internalization by distinct cytoskeletal pathways

¹ Departments of Pharmacology, Diabetes & Metabolic Diseases Research Center-HSC, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA
² Physiology & Biophysics, Diabetes & Metabolic Diseases Research Center-HSC, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA

^* Author for correspondence (e-mail: craig{at}pharm.sunysb.edu)

Accepted 18 September 2003

Insulin and ß-adrenergic agonists stimulate a rapid phosphorylation and sequestration of the ß₂-adrenergic receptors (ß₂ARs). Although the expectation was that a common pathway would be involved in the trafficking of the ß₂AR in response to either hormone, studies reported herein show the existence of unique cytoskeletal requirements for internalization/recycling of G-protein-coupled receptors, such as the ß₂AR. Treatment of human epidermoid carcinoma A431 cells with nocodazole, which binds tubulin monomer in vivo and catalyzes the depolymerization of microtubules, effectively blocks ß-adrenergic agonist-induced, but not insulin-induced, sequestration of ß₂ARs. Treatment with latrunculin-A, an agent that sequesters actin monomer and leads to loss of actin filaments, had no effect on the ability of ß-adrenergic agonists to stimulate internalization of ß₂ARs, but blocked the ability of insulin to stimulate counterregulation of ß₂ARs via internalization. Although nocodazole had no effect on insulin-stimulated sequestration of ß₂ARs, the recycling of the internalized receptors to the cell membrane was sensitive to depolymerization of microtubules by this agent. Latrunculin-A, by contrast, blocks the recycling of ß₂ARs internalized in response to ß-agonist, while attenuating recycling of receptors internalized in response to insulin stimulation. These data show the existence of unique cytoskeletal requirements for G-protein-coupled-receptor trafficking in response to agonist compared with a counterregulatory hormone, and for sequestration versus recycling of the receptors to the cell membrane.

Key words: G-protein-coupled receptors, Internalization, Counterregulation, Insulin, Agonist-induced, Trafficking

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