Glucagon-like peptide-2 (GLP-2) reduces
mouse gastric tone and small intestine transit, but its action on
large intestine motility is still unknown. The purposes of the present
study were 1) to examine the influence of GLP-2 on spontaneous
mechanical activity and on neurally evoked responses, by recording
intraluminal pressure from mouse isolated colonic segments; 2) to
characterize GLP-2 mechanism of action; and 3) to determine the
distribution of GLP-2 receptor (GLP-2R) in the mouse colonic
muscle coat by immunohistochemistry. Exogenous GLP-2 (0.1\u2013
300 nM) induced a concentration-dependent reduction of the spontaneous
mechanical activity, which was abolished by the desensitization
of GLP-2 receptor or by tetrodotoxin, a voltage-dependent
Na+-channel blocker. GLP-2 inhibitory effect was not affected by
Nomega-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor),
apamin (a blocker of small conductance Ca2+-dependent K+
channels), or [Lys1,Pro2,5,Arg3,4,Tyr6]VIP7\u201328 (a VIP receptor
antagonist), but it was prevented by atropine or pertussis toxin
(PTX), a Gi/o protein inhibitor. Proximal colon responses to electrical
field stimulation were characterized by nitrergic relaxation,
which was followed by cholinergic contraction. GLP-2 reduced
only the cholinergic evoked contractions. This effect was almost
abolished by GLP-2 receptor desensitization or PTX. GLP-2 failed
to affect the contractile responses to exogenous carbachol. GLP-2R
immunoreactivity (IR) was detected only in the neuronal cells of
both plexuses of the colonic muscle coat. More than 50% of
myenteric GLP-2R-IR neurons shared the choline acetyltransferase
IR. In conclusion, the activation of GLP-2R located on cholinergic
neurons may modulate negatively the colonic spontaneous and
electrically evoked contractions through inhibition of acetylcholine
release. The effect is mediated by Gi protein
