Mice Lacking M2 and M3 Muscarinic Acetylcholine Receptors Are Devoid of Cholinergic Smooth Muscle Contractions But Still Viable
Mice Lacking M2 and M3 Muscarinic Acetylcholine Receptors Are Devoid of Cholinergic Smooth Muscle Contractions But Still Viable
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DOI：
10.1523/jneurosci.22-24-10627.2002
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发表时间：
2002-12
期刊：
影响因子：
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通讯作者：
M. Matsui;Daisuke Motomura;T. Fujikawa;Jian Jiang;S. Takahashi;T. Manabe;M. Taketo
中科院分区：
文献类型：
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作者：
M. Matsui;Daisuke Motomura;T. Fujikawa;Jian Jiang;S. Takahashi;T. Manabe;M. Taketo
胆碱能药物通过刺激包括五种不同亚型（M1-M5）的毒蕈碱受体引起显著的平滑肌收缩。尽管这种收缩对自主器官很重要，但由于目前可用的毒蕈碱配体的选择性较差，每种亚型的作用尚未精确表征。在这里，我们产生了一个突变小鼠系（M2 - / - M3 - / -小鼠）缺乏参与这种胆碱能收缩的M2和M3受体。在体外，M2和M3受体对逼尿肌收缩的相对贡献分别为~ 5%和95%，对回肠纵肌收缩的相对贡献分别为~ 25%和75%。因此，M1、M4或m5受体似乎在这种收缩中不起作用。尽管在体外完全缺乏胆碱能收缩，M2 - / - M3 - / -小鼠仍能存活、生育，且无明显的肠道并发症。只有男性的膀胱扩张，这排除了胆碱能机制对女性排尿的主要贡献。因此，胆碱能机制在胃肠运动和女性排尿中是不可缺少的。在10 Hz电场刺激后，M2−/−M3−/−雌性回肠的非胆碱能输入增加，这可能是缺乏明显功能缺陷的原因。有趣的是，M2−/−M3−/−小鼠的瞳孔比M3缺乏小鼠小。结果表明M2在瞳孔扩张中的新作用，与众所周知的胆碱能收缩相反。这些结果共同表明，一个额外的机制在控制瞳孔收缩-扩张。
Cholinergic agents elicit prominent smooth muscle contractions via stimulation of muscarinic receptors that comprise five distinct subtypes (M1–M5). Although such contractions are important for autonomic organs, the role of each subtype has not been characterized precisely because of the poor selectivity of the currently available muscarinic ligands. Here, we generated a mutant mouse line (M2−/−M3−/− mice) lacking M2 and M3 receptors that are implicated in such cholinergic contractions. The relative contributions of M2 and M3 receptors in vitrowas ∼5 and 95% for the detrusor muscle contraction and ∼25 and 75% for the ileal longitudinal muscle contraction, respectively. Thus, M1, M4, or M5receptors do not seem to play a role in such contractions. Despite the complete lack of cholinergic contractions in vitro, M2−/−M3−/− mice were viable, fertile, and free of apparent intestinal complications. The urinary bladder was distended only in males, which excludes a major contribution by cholinergic mechanisms to the urination in females. Thus, cholinergic mechanisms are dispensable in gastrointestinal motility and female urination. After 10 Hz electrical field stimulation, noncholinergic inputs were found to be increased in the ileum of M2−/−M3−/− females, which may account for the lack of apparent functional deficits. Interestingly, the M2−/−M3−/− mice had smaller ocular pupils than M3-deficient mice. The results suggest a novel role of M2 in the pupillary dilation, contrary to the well known cholinergic constriction. These results collectively suggest that an additional mechanism operates in the control of pupillary constriction–dilatation.