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A more recent version of this article appeared on August 1, 2004 Originally published as MBC in Press, 10.1091/mbc.E03-11-0825 on May 28, 2004
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Submitted on November 18, 2003
Revised on May 11, 2004
Accepted on May 18, 2004
Departments of Laboratory Medicine and Pathobiology, and Medicine, University of Toronto, and The Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Canada M5G 2C4
Monitoring Editor: Jennifer Lippincott-Schwartz
The intestinotrophic and cytoprotective actions of GLP-2 are mediated by the GLP-2R, a member of the class II Glucagon-Secretin GPCR superfamily. Although native GLP-2 exhibits a short circulating half-life, long-acting degradation-resistant GLP-2 analogues are being evaluated for therapeutic use in human subjects. Accordingly, we examined the mechanisms regulating signaling, internalization and trafficking of the GLP-2R to identify determinants of receptor activation and desensitization. Heterologous cells expressing the transfected rat or human GLP-2R exhibited a rapid, dose-dependent, and prolonged desensitization of the GLP-2-stimulated cAMP response and a sustained GLP-2-induced decrease in levels of cell surface receptor. Surprisingly, inhibitors of clathrin-dependent endocytosis failed to significantly decrease GLP-2R internalization, whereas cholesterol sequestration inhibited ligand-induced receptor internalization and potentiated homologous desensitization. The hGLP-2R localized to both Triton X-100 soluble and insoluble (lipid raft) cellular fractions and colocalized transiently with the lipid raft marker caveolin-1. Although GLP-2R endocytosis was dependent on lipid raft integrity, the receptor transiently associated with GFP-EEA1 positive vesicles and inhibitors of endosomal acidification attenuated the reappearance of the GLP-2R on the cell surface. Our data demonstrate that GLP-2R desensitization and raft-dependent trafficking represent distinct and independent cellular mechanisms and provide new evidence implicating the importance of a clathrin- and dynamin-independent, lipid-raft-dependent pathway for homologous GPCR internalization.
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