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J. Biol. Chem., Vol. 280, Issue 23, 22124-22134, June 10, 2005

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The Glucagon-like Peptide-2 Receptor C Terminus Modulates -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**

From the Departments of Laboratory Medicine and Pathobiology, and ^**Medicine, University of Toronto, The Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto M5G 2C4, Canada

Classic models of receptor desensitization and internalization have been largely based on the behavior 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 protein kinase A-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 -arrestin-2. Site-directed mutagenesis identified specific amino acid residues within the distal GLP-2R C terminus that mediate the stable association with -arrestin-2. Surprisingly, although the truncated mutant receptors failed to interact with -arrestin-2, they underwent homologous desensitization and subsequent resensitization with kinetics similar to that observed with the wild-type GLP-2R. Our data suggest that, although 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 suggest that GLP-2 receptor signaling has evolved unique structural and functional mechanisms for control of receptor trafficking, desensitization, and resensitization.

Received for publication, January 4, 2005 , and in revised form, March 14, 2005.

^* The work was supported in part by operating grants from the Canadian Institutes of Health Research (CIHR), the National Cancer Institute of Canada, and the Ontario Research and Development Challenge Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains additional text.

^¶ Supported by a CIHR Canadian Graduate Scholarship Doctoral Award and a grant from the Banting and Best Diabetes Centre/Novo-Nordisk.

^|| Supported by a postdoctoral fellowship award from the Banting and Best Diabetes Centre and the McLaughlin Center for Molecular Medicine.

Supported by a Canada Research Chair in Regulatory Peptides. To whom correspondence should be addressed: Toronto General Hospital Banting and Best Diabetes Centre, 200 Elizabeth St., MBRC4R-402, Toronto M5G 2C4, Canada. Tel.: 416-340-4125; Fax: 416-978-4108; E-mail: d.drucker{at}utoronto.ca.

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