Butyrylcholinesterase and the control of synaptic responses in acetylcholinesterase knockout mice
Butyrylcholinesterase and the control of synaptic responses in acetylcholinesterase knockout mice
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DOI：
10.1016/j.lfs.2007.03.011
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发表时间：
2007-05-30
期刊：
影响因子：
6.1
通讯作者：
Molgo, Jordi
中科院分区：
文献类型：
--
作者：
Girard, Emmanuelle;Bernard, Veronique;Molgo, Jordi
在神经肌肉接头(NMJ)，乙酰胆碱酯酶(AChE)和丁基胆碱酯酶(BChE)可以水解乙酰胆碱(ACh)。已知释放的ACh量子在狭窄的突触缝隙中迅速扩散，成对的ACh分子协作打开终板通道。在通过缝隙扩散的过程中，或从肌肉烟碱型ACh受体(NAChRs)释放出来后，大多数ACh分子被高度集中在NMJ的AchE水解。小鼠基因组学的进展为评估特定胆碱酯酶在突触传递中的作用提供了新的方法。AChE基因敲除小鼠(AChE-KO)为研究AChE活性的完全取消和BChE的作用提供了一个有价值的工具。AChE-KO小鼠存活到成年，对BChE抑制剂的敏感性增加，这表明BChE活性促进了它们的生存，并补偿了AChE功能。我们的结果表明，BChE存在于野生型和AChE-KO成熟肌肉的终板区。在野生型和AChE-KO结中，焦点记录的微小终板电流的衰减时间常数分别为1.04+/-0.06ins和5.4ms+/-0.3ms，且不受BChE特异性抑制剂的影响，表明BChE不限制终板nAChRs上ACh的持续时间。抑制BChE可减少AChE-KO NMJ诱发的乙酰胆碱酯酶量子释放。ACh释放的减少可以解释AChE-Ko小鼠对BChE抑制剂最敏感的原因。已知BChE定位于突触周围雪旺细胞，我们的结果有力地表明BChE在NMJ的作用是保护神经末梢免受过量ACh的影响。(C)2007 Elsevier Inc.保留所有权利。
At the neuromuscular junction (NMJ) acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) can hydrolyze acetylcholine (ACh). Released ACh quanta are known to diffuse rapidly across the narrow synaptic cleft and pairs of ACh molecules cooperate to open endplate channels. During their diffusion through the cleft, or after being released from muscle nicotinic ACh receptors (nAChRs), most ACh molecules are hydrolyzed by AChE highly concentrated at the NMJ. Advances in mouse genomics offered new approaches to assess the role of specific cholinesterases involved in synaptic transmission. AChE knockout mice (AChE-KO) provide a valuable tool for examining the complete abolition of AChE activity and the role of BChE. AChE-KO mice live to adulthood, and exhibit an increased sensitivity to BChE inhibitors, suggesting that BChE activity facilitated their survival and compensated for AChE function. Our results show that BChE is present at the endplate region of wildtype and AChE-KO mature muscles. The decay time constant of focally recorded miniature endplate currents was 1.04 +/- 0.06 ins in wild-type junctions and 5.4 ms +/- 0.3 ms in AChE-KO junctions, and remained unaffected by BChE-specific inhibitors, indicating that BChE is not limiting ACh duration on endplate nAChRs. Inhibition of BChE decreased evoked quantal ACh release in AChE-KO NMJs. This reduction in ACh release can explain the greatest sensitivity of AChE-kO mice to BChE inhibitors. BChE is known to be localized in perisynaptic Schwann cells, and our results strongly suggest that BChE's role at the NMJ is to protect nerve terminals from an excess of ACh. (c) 2007 Elsevier Inc. All rights reserved.