Extrahypothalamic expression of the glucagon-like peptide-2 receptor is coupled to reduction of glutamate-induced cell death in cultured hippocampal cells

Endocrinology. 2004 Jul;145(7):3495-506. doi: 10.1210/en.2004-0100. Epub 2004 Apr 1.


Proglucagon-derived glucagon-like peptide-2 (GLP-2) is liberated in enteroendocrine cells and neurons. GLP-2 regulates energy absorption and epithelial integrity in the gastrointestinal tract, whereas GLP-2 action in the central nervous system remains poorly defined. We identified proglucagon and GLP-2 receptor (GLP-2R) mRNA transcripts by RT-PCR in multiple regions of the developing and adult rat central nervous system. GLP-2R mRNA transcripts were localized by in situ hybridization to the hippocampus, hypothalamus, nucleus of the solitary tract, parabrachial nucleus, supramammillary nucleus, and substantia nigra. The bioactive form of GLP-2, GLP-2-(1-33) was detected by RIA and HPLC analysis in the fetal and adult brainstem and hypothalamus. GLP-2 stimulated increases in cAMP accumulation in postnatal d 8, but not embryonic d 14, dispersed neonatal rat brainstem tissues. The actions of GLP-2 were independent of the GLP-1R antagonist exendin-(9-39), and GLP-2 stimulated cAMP accumulation in hippocampal cell cultures from both wild-type and GLP-1R(-/-) mice. GLP-2 significantly reduced glutamate-induced excitotoxic injury in hippocampal cells via a protein kinase A-dependent pathway, but had no effect on the rate of cell proliferation. These findings establish the presence of a functional GLP-2-GLP-2R axis in the developing rodent brain and demonstrate that GLP-2 exerts cytoprotective actions in cells derived from the central nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Female
  • Fetus
  • Gene Expression Regulation, Developmental
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptides
  • Glutamic Acid / toxicity
  • Hippocampus / cytology*
  • Hippocampus / embryology
  • In Vitro Techniques
  • Male
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Peptides / genetics*
  • Peptides / metabolism
  • Pregnancy
  • Rats
  • Rats, Wistar
  • Receptors, Glucagon / genetics*
  • Receptors, Glucagon / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-1 Receptor
  • Peptides
  • Receptors, Glucagon
  • Glutamic Acid
  • Glucagon-Like Peptides
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases