M1-M5毒蕈碱受体敲除小鼠作为研究毒蕈碱胆碱能系统生理作用的新工具。

J. Wess, A. Duttaroy, Weilie Zhang, J. Gomeza, Yinghong Cui, Tsuyoshi Miyakawa, F. Bymaster, L. Mckinzie, C. Felder, Kathryn G. Lamping, F. Faraci, Chu-Xia Deng, Masahisa Yamada
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引用次数: 107

摘要

大量证据表明,毒蕈碱乙酰胆碱受体(mAChRs)在调节中枢和周围神经系统许多重要功能的活动中起着关键作用。然而,鉴定单个mAChR亚型(M(1)-M(5))的生理和病理生理作用已被证明是一项艰巨的任务,主要是由于缺乏具有高度受体亚型选择性的配体,以及大多数组织和器官表达多种mAChR。为了克服这些困难,我们使用基因靶向技术产生含有M(1)-M(5) mAChR基因失活突变的突变小鼠系。不同的mAChR突变小鼠和相应的野生型对照动物进行了一系列的生理、药理学、行为、生化和神经化学测试。M(1)-M(5) mAChR突变小鼠存活,繁殖正常。然而,每个突变系都表现出特定的功能缺陷,这表明每个mAChR亚型介导不同的生理功能。这些结果将为毒蕈碱类新药的合理开发提供新的思路。
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M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system.
A large body of evidence indicates that muscarinic acetylcholine receptors (mAChRs) play critical roles in regulating the activity of many important functions of the central and peripheral nervous systems. However, identification of the physiological and pathophysiological roles of the individual mAChR subtypes (M(1)-M(5)) has proven a difficult task, primarily due to the lack of ligands endowed with a high degree of receptor subtype selectivity and the fact that most tissues and organs express multiple mAChRs. To circumvent these difficulties, we used gene targeting technology to generate mutant mouse lines containing inactivating mutations of the M(1)-M(5) mAChR genes. The different mAChR mutant mice and the corresponding wild-type control animals were subjected to a battery of physiological, pharmacological, behavioral, biochemical, and neurochemical tests. The M(1)-M(5) mAChR mutant mice were viable and reproduced normally. However, each mutant line displayed specific functional deficits, suggesting that each mAChR subtype mediates distinct physiological functions. These results should offer new perspectives for the rational development of novel muscarinic drugs.
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