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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice.
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Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice.

机译：毒蕈碱型乙酰胆碱受体敲除小鼠中的毒蕈碱型乙酰胆碱受体功能的调节。

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Acetylcholinesterase (AChE) hydrolyzes acetylcholine to terminate cholinergic neurotransmission. Overstimulation of cholinergic receptors by excess acetylcholine is known to be lethal. However, AChE knockout mice live to adulthood, although they have weak muscles, do not eat solid food, and die early from seizures. We wanted to know what compensatory factors allowed these mice to survive. We had previously shown that their butyrylcholinesterase activity was normal and had not increased. In this report, we tested the hypothesis that AChE-/- mice adapted to the absence of AChE by downregulating cholinergic receptors. Receptor downregulation is expected to reduce sensitivity to agonists and to increase sensitivity to antagonists. Physiological response to the muscarinic agonists, oxotremorine (OXO) and pilocarpine, showed that AChE-/- mice were resistant to OXO-induced hypothermia, tremor, salivation, and analgesia, and to pilocarpine-induced seizures. AChE+/- mice had an intermediate response. The muscarinic receptor binding sites measured with [3H]quinuclinyl benzilate, as well as the protein levels of M1, M2, and M4 receptors measured with specific antibodies on Western blots, were reduced to be approximately 50% in AChE-/- brain. However, mRNA levels for muscarinic receptors were unchanged. These results indicate that one adaptation to the absence of AChE is downregulation of muscarinic receptors, thus reducing response to cholinergic stimulation.
机译：乙酰胆碱酯酶（AChE）水解乙酰胆碱以终止胆碱能神经传递。过量的乙酰胆碱对胆碱能受体的过度刺激是致命的。但是，AChE基因敲除小鼠虽然肌肉无力，不吃固体食物并且会因癫痫发作而早死，但它们能活到成年。我们想知道哪些补偿因素使这些小鼠得以存活。先前我们已经表明它们的丁酰胆碱酯酶活性是正常的，并且没有增加。在本报告中，我们测试了AChE-/-小鼠通过下调胆碱能受体来适应AChE缺失的假设。预期受体下调会降低对激动剂的敏感性并增加对拮抗剂的敏感性。对毒蕈碱激动剂oxotremorine（OXO）和毛果芸香碱的生理反应表明，AChE-/-小鼠对OXO引起的体温过低，震颤，流涎和镇痛以及毛果芸香碱引起的癫痫发作具有抵抗力。 AChE +/-小鼠具有中等反应。在AChE-/-脑中，用[3H]喹啉烷基苯甲酸酯测量的毒蕈碱受体结合位点以及用特异性抗体在Western印迹上测量的M1，M2和M4受体的蛋白水平降低了约50％。但是，毒蕈碱受体的mRNA水平没有变化。这些结果表明，对AChE缺乏的一种适应是毒蕈碱受体的下调，从而降低了对胆碱能刺激的反应。

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