McDonagh Sean C, Lee Jenny, Izzo Angelo, Brubaker Patricia L
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Am J Physiol Gastrointest Liver Physiol. 2007 Aug;293(2):G461-8. doi: 10.1152/ajpgi.00424.2006. Epub 2007 Jun 21.
The intestinal glucagon-like peptides GLP-1 and GLP-2 inhibit intestinal motility, whereas GLP-2 also stimulates growth of the intestinal mucosa. However, the mechanisms of action of these peptides in the intestine remain poorly characterized. To determine the role of the enteric nervous system in the actions of GLP-1 and GLP-2 on the intestine, the glial cell line-derived neurotropic factor family receptor alpha(2) (GFRalpha2) knockout (KO) mouse was employed. The mice exhibited decreased cholinergic staining, as well as reduced mRNA transcripts for substance P-ergic excitatory motoneurons in the enteric nervous system (ENS) (P < 0.05). Examination of parameters of intestinal growth (including small and large intestinal weight and small intestinal villus height, crypt depth, and crypt cell proliferation) demonstrated no differences between wild-type and KO mice in either basal or GLP-2-stimulated mucosal growth. Nonetheless, KO mice exhibited reduced numbers of synaptophysin-positive enteroendocrine cells (P < 0.05), as well as a markedly impaired basal gastrointestinal (GI) transit rate (P < 0.05). Furthermore, acute administration of GLP-1 and GLP-2 significantly inhibited transit rates in wild-type mice (P < 0.05-0.01) but had no effect in GFRalpha2 KO mice. Despite these changes, expression of mRNA transcripts for the GLP receptors was not reduced in the ENS of KO animals, suggesting that GLP-1 and -2 modulate intestinal transit through enhancement of inhibitory input to cholinergic/substance P-ergic excitatory motoneurons. Together, these findings demonstrate a role for GFRalpha2-expressing enteric neurons in the downstream signaling of the glucagon-like peptides to inhibit GI motility, but not in intestinal growth.
肠道胰高血糖素样肽GLP - 1和GLP - 2可抑制肠道蠕动，而GLP - 2还能刺激肠黏膜生长。然而，这些肽在肠道中的作用机制仍不清楚。为了确定肠神经系统在GLP - 1和GLP - 2对肠道作用中的作用，研究采用了胶质细胞系衍生的神经营养因子家族受体α2（GFRα2）基因敲除（KO）小鼠。这些小鼠的胆碱能染色减少，肠神经系统（ENS）中P物质能兴奋性运动神经元的mRNA转录本也减少（P < 0.05）。对肠道生长参数（包括小肠和大肠重量、小肠绒毛高度、隐窝深度和隐窝细胞增殖）的检测表明，野生型和KO小鼠在基础状态或GLP - 2刺激的黏膜生长方面均无差异。尽管如此，KO小鼠的突触素阳性肠内分泌细胞数量减少（P < 0.05），基础胃肠（GI）转运速率也明显受损（P < 0.05）。此外，急性给予GLP - 1和GLP - 2可显著抑制野生型小鼠的转运速率（P < 0.05 - 0.01），但对GFRα2 KO小鼠无影响。尽管有这些变化，KO动物的ENS中GLP受体的mRNA转录本表达并未降低，这表明GLP - 1和 - 2通过增强对胆碱能/P物质能兴奋性运动神经元的抑制性输入来调节肠道转运。总之，这些发现表明，表达GFRα2的肠神经元在胰高血糖素样肽的下游信号传导中发挥作用，以抑制胃肠蠕动，但对肠道生长无作用。
