Roles of M2 and M3 muscarinic receptors in cholinergic nerve-induced contractions in mouse ileum studied with receptor knockout mice
Roles of M2 and M3 muscarinic receptors in cholinergic nerve-induced contractions in mouse ileum studied with receptor knockout mice
复制标题
DOI：
10.1038/sj.bjp.0706955
复制
发表时间：
2006-12-01
影响因子：
7.3
通讯作者：
Komori, S.
中科院分区：
文献类型：
--
作者：
Unno, T.;Matsuyama, H.;Komori, S.
背景与目的：M-2和M-3毒蕈碱受体在胃肠道神经源性胆碱能收缩中的功能作用尚待阐明。为了解决这个问题，我们使用缺乏M-2或M-3受体亚型的突变小鼠研究了胆碱能神经诱导的回肠收缩。实验方法：在M-2敲除（KO）、M-3-KO、M-2/ m -3双KO和野生型小鼠的回肠节段等长记录对跨壁电（TE）刺激的收缩反应。关键结果：在野生型、M-2-KO或M-3-KO小鼠制剂中，2-50 Hz频率依赖性的TE刺激诱发了快速、短暂的收缩，随后是较慢、较长的收缩。河豚毒素阻断了最初和后来的收缩，而阿托品仅抑制了最初的收缩。野生型小鼠初始胆碱能收缩明显大于M-2-KO和M-3-KO小鼠；50 Hz时的平均振幅分别为70mM K+诱发收缩的91%、74%和68%。百日咳毒素预处理可阻断M-3-KO小鼠胆碱能收缩，但对M-2-KO小鼠无抑制作用。野生型制剂中胆碱能收缩仍然存在，但在10-50 Hz时其大小减少了20-30%。在M-2/ m -3双KO小鼠中，TE刺激仅引起缓慢的非胆碱能性收缩，其大小明显大于其他三种小鼠品系。结论和意义：这些结果表明，M-2和M-3受体参与了小鼠回肠胆碱能收缩的调节，但后者的作用更大。我们的数据还表明，M-2和M-3受体的缺乏导致肠道平滑肌非胆碱能兴奋性神经支配的上调。
Background and purpose: The functional roles of M-2 and M-3 muscarinic receptors in neurogenic cholinergic contractions in gastrointestinal tracts remain to be elucidated. To address this issue, we studied cholinergic nerve-induced contractions in the ileum using mutant mice lacking M-2 or M-3 receptor subtypes.Experimental approach: Contractile responses to transmural electrical (TE) stimulation were isometrically recorded in ileal segments from M-2-knockout (KO), M-3-KO, M-2/M-3-double KO, and wild-type mice.Key results: TE stimulation at 2-50 Hz frequency-dependently evoked a fast, brief contraction followed by a slower, longer one in wild-type, M-2-KO or M-3-KO mouse preparations. Tetrodotoxin blocked both the initial and later contractions, while atropine only inhibited the initial contractions. The initial cholinergic contractions were significantly greater in wild-type than M-2-KO or M-3-KO mice; the respective mean amplitudes at 50 Hz were 91, 74 and 68% of 70mM K+ -induced contraction. Pretreatment with pertussis toxin blocked the cholinergic contractions in M-3-KO but not in M-2-KO mice. Cholinergic contractions also remained in wild-type preparations, but their sizes were reduced by 20-30% at 10-50 Hz. In M-2/M-3-double KO mice, TE stimulation evoked only slow, noncholinergic contractions, which were significantly greater in sizes than in any of the other three mouse strains.Conclusion and Implications: These results demonstrate that M-2 and M-3 receptors participate in mediating cholinergic contractions in mouse ileum with the latter receptors assuming a greater role. Our data also suggest that the lack of both M-2 and M-3 receptors causes upregulation of noncholinergic excitatory innervation of the gut smooth muscle.