This Article Full Text Full Text (PDF) All Versions of this Article: 144/10/4385    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Walsh, N. A. Articles by Brubaker, P. L. Search for Related Content PubMed PubMed Citation Articles by Walsh, N. A. Articles by Brubaker, P. L. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL

Glucagon-Like Peptide-2 Receptor Activation in the Rat Intestinal Mucosa

Departments of Physiology (N.A.W., M.P.D., Y.A., P.L.B.) and Medicine (D.J.D., P.L.B.), University of Toronto, Toronto, Canada M5S 1A8; and the Banting and Best Diabetes Centre (B.Y., D.J.D.), The Toronto General Hospital, University of Toronto, Toronto, Canada M5G 2C4

Address all correspondence and requests for reprints to: Dr. P. L. Brubaker, Room 3366, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail: p.brubaker{at}utoronto.ca.

Glucagon-like peptide-2 (GLP-2) increases small intestinal growth and function in rodents and human subjects. GLP-2 exerts its effects through a seven-transmembrane domain, G protein-coupled receptor (GLP-2R), stimulating cAMP generation and activating protein kinase A signaling in heterologous cell lines transfected with the GLP-2R. As intestinal cell lines expressing the GLP-2R have not been identified, we developed methods for studying GLP-2R signaling in the rat small intestinal mucosa in vitro. Isolated rat intestinal mucosal cells expressed mRNA transcripts for the GLP-2R, as well as for chromogranin A and ß-tubulin III, markers for enteroendocrine and neural cells, respectively. cAMP production in response to [Gly²]GLP-2, a degradation-resistant analog of GLP-2, was maximal at 10^-11 M (268 ± 93% of control, P < 0.001), with reduced cAMP accumulation observed at higher doses. The cAMP response was diminished by pretreatment with 10^-9 M GLP-2, and was abolished by pretreatment with 10^-6 M GLP-2 (P < 0.05), indicating receptor desensitization. GLP-2 treatment of isolated mucosal cells increased ³H-thymidine incorporation (to 128 ± 8% of controls, P < 0.05), and this was prevented by inhibition of the protein kinase A pathway with H89. In contrast, GLP-2 did not affect p44/p42 MAPK phosphorylation or the levels of cytosolic calcium in the mucosal cell preparation. These results provide the first evidence that activation of the endogenous rat mucosal GLP-2 receptor is linked to activation of a cAMP/protein kinase A-dependent, growth-promoting pathway in vitro.

This article has been cited by other articles:

				P. E. Dube, K. J. Rowland, and P. L. Brubaker Glucagon-Like Peptide-2 Activates -Catenin Signaling in the Mouse Intestinal Crypt: Role of Insulin-Like Growth Factor-I Endocrinology, January 1, 2008; 149(1): 291 - 301. [Abstract] [Full Text] [PDF]

				P. E. Dube and P. L. Brubaker Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E460 - E465. [Abstract] [Full Text] [PDF]

				D. L. Sigalet, L. E. Wallace, J. J. Holst, G. R. Martin, T. Kaji, H. Tanaka, and K. A. Sharkey Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2 Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G211 - G221. [Abstract] [Full Text] [PDF]

				Y. Anini, A. Izzo, G. Y. Oudit, P. H. Backx, and P. L. Brubaker Role of phosphatidylinositol-3 kinase-{gamma} in the actions of glucagon-like peptide-2 on the murine small intestine Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1599 - E1606. [Abstract] [Full Text] [PDF]

				D. W. Nelson, J. W. Sharp, M. S. Brownfield, H. E. Raybould, and D. M. Ney Localization and Activation of Glucagon-Like Peptide-2 Receptors on Vagal Afferents in the Rat Endocrinology, May 1, 2007; 148(5): 1954 - 1962. [Abstract] [Full Text] [PDF]

				D. G. Burrin, B. Stoll, X. Guan, L. Cui, X. Chang, and D. Hadsell GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E281 - E291. [Abstract] [Full Text] [PDF]

				K.-A. Kim, M. Kakitani, J. Zhao, T. Oshima, T. Tang, M. Binnerts, Y. Liu, B. Boyle, E. Park, P. Emtage, et al. Mitogenic Influence of Human R-Spondin1 on the Intestinal Epithelium Science, August 19, 2005; 309(5738): 1256 - 1259. [Abstract] [Full Text] [PDF]

				P. A. Kitchen, R. A. Goodlad, A. J. FitzGerald, N. Mandir, M. A. Ghatei, S. R. Bloom, J. Berlanga-Acosta, R. J. Playford, A. Forbes, and J. R.F. Walters Intestinal Growth in Parenterally-Fed Rats Induced by the Combined Effects of Glucagon-like Peptide 2 and Epidermal Growth Factor JPEN J Parenter Enteral Nutr, July 1, 2005; 29(4): 248 - 254. [Abstract] [Full Text] [PDF]

				G. R. Martin, L. E. Wallace, B. Hartmann, J. J. Holst, L. Demchyshyn, K. Toney, and D. L. Sigalet Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome Am J Physiol Gastrointest Liver Physiol, March 1, 2005; 288(3): G431 - G438. [Abstract] [Full Text] [PDF]

				D. G. Burrin, B. Stoll, X. Guan, L. Cui, X. Chang, and J. J. Holst Glucagon-Like Peptide 2 Dose-Dependently Activates Intestinal Cell Survival and Proliferation in Neonatal Piglets Endocrinology, January 1, 2005; 146(1): 22 - 32. [Abstract] [Full Text] [PDF]

				L. L. Baggio, J.-G. Kim, and D. J. Drucker Chronic Exposure to GLP-1R Agonists Promotes Homologous GLP-1 Receptor Desensitization In Vitro but Does Not Attenuate GLP-1R-Dependent Glucose Homeostasis In Vivo Diabetes, December 1, 2004; 53(suppl_3): S205 - S214. [Abstract] [Full Text] [PDF]

				A. Howard, R. A. Goodlad, J. R. F. Walters, D. Ford, and B. H. Hirst Increased Expression of Specific Intestinal Amino Acid and Peptide Transporter mRNA in Rats Fed by TPN Is Reversed by GLP-2 J. Nutr., November 1, 2004; 134(11): 2957 - 2964. [Abstract] [Full Text] [PDF]

				J. L. Estall, B. Yusta, and D. J. Drucker Lipid Raft-dependent Glucagon-like Peptide-2 Receptor Trafficking Occurs Independently of Agonist-induced Desensitization Mol. Biol. Cell, August 1, 2004; 15(8): 3673 - 3687. [Abstract] [Full Text] [PDF]

				G. R. Martin, L. E. Wallace, and D. L. Sigalet Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome Am J Physiol Gastrointest Liver Physiol, June 1, 2004; 286(6): G964 - G972. [Abstract] [Full Text] [PDF]