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A more recent version of this article appeared on June 10, 2005
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M500078200v1
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Papers In Press, published online ahead of print April 6, 2005
J. Biol. Chem, 10.1074/jbc.M500078200
Submitted on January 4, 2005
Revised on March 14, 2005
Accepted on April 6, 2005

The GLP-2R C-terminus modulates beta-arrestin-2 association, but is dispensable for ligand-induced desensitization, endocytosis and G-protein-dependent effector activation

Jennifer L. Estall, Jacqueline A. Koehler, Bernardo Yusta, and Daniel J. Drucker

Department of Medicine, Toronto General Hospital, Toronto, Ontario M5G2C4

Corresponding Author: d.drucker{at}utoronto.ca

Classical models of receptor desensitization and internalization have been largely based on the behaviour of Family A G-protein coupled receptors (GPCRs). The glucagon-like peptide-2 receptor (GLP-2R) is a member of the Family B Glucagon-Secretin GPCR family, which exhibit significant sequence and structural differences from the Family A receptors in their intracellular and extracellular domains. To identify structural motifs that regulate GLP-2R signaling and cell surface receptor expression, we analyzed the functional properties of a series of mutant GLP-2Rs. The majority of the C-terminal receptor tail was dispensable for GLP-2-induced cAMP accumulation, ERK1/2 activation, and endocytosis in transfected cells. However, progressive truncation of the C-terminus reduced cell surface receptor expression, altered agonist-induced GLP-2R trafficking, and abrogated PKA-mediated heterologous receptor desensitization. Elimination of the distal 21 amino acids of the receptor was sufficient to promote constitutive receptor internalization and prevent agonist-induced recruitment of beta-arrestin-2. Site-directed mutagenesis identified specific amino acid residues within the distal GLP-2R C-terminus that mediate the stable association with beta-arrestin-2. Surprisingly, although the truncated mutant receptors failed to interact with beta-arrestin-2, they underwent homologous desensitization and subsequent resensitization with kinetics similar to that observed with the wild-type GLP-2R. Our data suggests that while the GLP-2R C-terminus is not required for coupling to cellular machinery regulating signaling or desensitization, it may serve as a sorting signal for intracellular trafficking. Taken together with the previously demonstrated clathrin and dynamin-independent, lipid-raft-dependent pathways for internalization, our data suggests that GLP-2 receptor signaling has evolved unique structural and functional mechanisms for control of receptor trafficking, desensitization, and resensitization


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