Glucagon-like peptide-2 (GLP-2) is
an important neuroendocrine peptide in intestinal physiology. It influences
digestion, absorption, epithelial growth, motility, and blood
flow. We studied involvement of GLP-2 in intestinal mucosal secretory
behavior. Submucosal-mucosal preparations from guinea pig
ileum were mounted in Ussing chambers for measurement of shortcircuit
current (Isc) as a surrogate for chloride secretion. GLP-2 action
on neuronal release of acetylcholine was determined with ELISA.
Enteric neuronal expression of the GLP-2 receptor (GLP-2R) was
studied with immunohistochemical methods. Application of GLP-2
(0.1–100 nM) to the serosal or mucosal side of the preparations
evoked no change in baseline Isc and did not alter transepithelial ionic
conductance. Transmural electrical field stimulation (EFS) evoked
characteristic biphasic increases in Isc, with an initially rapid rising
phase followed by a sustained phase. Application of GLP-2 reduced
the EFS-evoked biphasic responses in a concentration-dependent
manner. The GLP-2R antagonist GLP-2-(3-33) significantly reversed
suppression of the EFS-evoked responses by GLP-2. Tetrodotoxin,
scopolamine, and hexamethonium, but not vasoactive intestinal peptide
type 1 receptor (VPAC1) antagonist abolished or reduced to near
zero the EFS-evoked responses. GLP-2 suppressed EFS-evoked acetylcholine
release as measured by ELISA. Pretreatment with GLP-2-
(3-33) offset this action of GLP-2. In the submucosal plexus, GLP-2R
immunoreactivity (-IR) was expressed in choline acetyltransferase-IR
neurons, somatostatin-IR neurons, neuropeptide Y-IR neurons, and
vasoactive intestinal peptide-IR neurons. We conclude that submucosal
neurons in the guinea pig ileum express GLP-2R. Activation of
GLP-2R decreases neuronally evoked epithelial chloride secretion by
suppressing acetylcholine release from secretomotor neurons