Glucagon-like peptide-2 receptor activation in the rat intestinal mucosa

Endocrinology. 2003 Oct;144(10):4385-92. doi: 10.1210/en.2003-0309. Epub 2003 Jul 3.


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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Chromogranin A
  • Chromogranins / genetics
  • Cyclic AMP / biosynthesis
  • Cytosol / metabolism
  • Dose-Response Relationship, Drug
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptides
  • Intestinal Mucosa / metabolism*
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Osmolar Concentration
  • Peptides / administration & dosage
  • Phosphorylation / drug effects
  • Protein Isoforms / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred F344
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism*
  • Thymidine / metabolism
  • Tubulin / genetics


  • Chromogranin A
  • Chromogranins
  • GLP1R protein, human
  • Glp1r protein, rat
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-1 Receptor
  • Peptides
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Glucagon
  • Tubulin
  • Glucagon-Like Peptides
  • Cyclic AMP
  • Mitogen-Activated Protein Kinases
  • Calcium
  • Thymidine