Haberberger Rainer, Schultheiss Gerhard, Diener Martin
Institut für Anatomie und Zellbiologie, Justus-Liebig-Universität Giessen, D-35392 Giessen, Germany.
Eur J Pharmacol. 2006 Jan 20;530(3):229-33. doi: 10.1016/j.ejphar.2005.11.055. Epub 2006 Jan 6.
Cholinergically induced intestinal anion secretion is generally believed to be caused by stimulation of epithelial muscarinic M3 receptors, whereas muscarinic M1 receptors are thought to be localized primarily on enteric neurons. In order to test this assumption, carbachol-stimulated Cl- secretion across distal colon, measured as increase in short-circuit current (I(sc)), was compared between M1-knockout (M1R-KO) and M3-knockout (M3R-KO) mice. Surprisingly, the maximal increase in I(sc) evoked by carbachol was more than twice as large in M3R-KO compared to M1R-KO mice. This difference was not due to a reduced secretory capacity of the epithelium from M3R-KO animals, as forskolin stimulated a similar maximal I(sc) in both types of animals. The neurotoxin tetrodotoxin diminished, but did not abolish the secretory response evoked by carbachol in M3R-KO distal colon, suggesting the existence of epithelial muscarinic receptors other than the type M3. Furthermore, in muscarinic receptor wild-type animals, the muscarinic M1 receptor antagonist pirenzepine inhibited the carbachol-stimulated I(sc) by more than 70% suggesting the presence of epithelial muscarinic M1 receptors; a conclusion, which was confirmed by the identification of mRNA for muscarinic M1 receptors in isolated crypts from wild-type colon. Consequently, epithelial muscarinic receptors from the type M1 contribute to cholinergically induced ion secretion in mouse colon.
一般认为，胆碱能诱导的肠道阴离子分泌是由上皮毒蕈碱M3受体的刺激引起的，而毒蕈碱M1受体主要定位于肠神经元。为了验证这一假设，比较了M1基因敲除（M1R-KO）小鼠和M3基因敲除（M3R-KO）小鼠中，以短路电流（I(sc)）增加来衡量的卡巴胆碱刺激的远端结肠氯离子分泌情况。令人惊讶的是，与M1R-KO小鼠相比，卡巴胆碱在M3R-KO小鼠中引起的I(sc)最大增加量是其两倍多。这种差异并不是由于M3R-KO动物上皮分泌能力的降低，因为福斯可林在两种动物中刺激产生的最大I(sc)相似。神经毒素河豚毒素减少了，但并没有消除卡巴胆碱在M3R-KO远端结肠中引起的分泌反应，这表明存在除M3型以外的上皮毒蕈碱受体。此外，在毒蕈碱受体野生型动物中，毒蕈碱M1受体拮抗剂哌仑西平抑制卡巴胆碱刺激的I(sc)超过70%，这表明存在上皮毒蕈碱M1受体；这一结论通过在野生型结肠分离隐窝中鉴定毒蕈碱M1受体的mRNA得到了证实。因此，M1型上皮毒蕈碱受体有助于小鼠结肠中胆碱能诱导的离子分泌。
