Upregulation of α7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides
Upregulation of α7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides
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DOI：
10.1371/journal.pone.0004846
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发表时间：
2009-03-16
期刊：
影响因子：
3.7
通讯作者：
Greenfield, Susan A.
中科院分区：
文献类型：
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作者：
Bond, Cherie E.;Zimmermann, Martina;Greenfield, Susan A.
背景：众所周知，α-7 烟碱乙酰胆碱受体（α 7-nAChR）是一种有效的钙离子载体，在大脑中与兴奋性毒性有关，因此与阿尔茨海默病等神经退行性疾病的潜在机制有关。先前的研究表明，这种受体的活性可能会通过暴露于乙酰胆碱酯酶 C 末端区域的肽片段而改变。本研究旨在确定观察到的功能变化是否可归因于肽与 α 7-nAChR 的结合相互作用，或肽对受体表达的调节。方法/主要发现：本研究提供的证据表明，源自乙酰胆碱酯酶 C 末端的两种肽不仅选择性取代 α 7-nAChR 上的特定金环蛇毒素结合，而且还改变其熟悉配体（包括替代内源激动剂）的受体结合特性胆碱。具有更长期意义的是，这些肽还诱导 α 7-nAChR mRNA 和蛋白质表达上调，并增强受体向质膜的运输。结论/意义：本文报告的结果表明 α 7-nAChR 与乙酰胆碱酯酶的非酶功能之间存在迄今未知的关系，由其 C 末端结构域独立介导。这种相互作用可能被证明是有价值的药理学工具，促进理解和对抗神经变性过程的新方法。
Background: The alpha-7 nicotinic acetylcholine receptor (alpha 7-nAChR) is well known as a potent calcium ionophore that, in the brain, has been implicated in excitotoxicity and hence in the underlying mechanisms of neurodegenerative disorders such as Alzheimer's disease. Previous research implied that the activity of this receptor may be modified by exposure to a peptide fragment derived from the C-terminal region of the enzyme acetylcholinesterase. This investigation was undertaken to determine if the functional changes observed could be attributed to peptide binding interaction with the alpha 7-nAChR, or peptide modulation of receptor expression.Methodology/Principal Findings: This study provides evidence that two peptides derived from the C-terminus of acetylcholinesterase, not only selectively displace specific bungarotoxin binding at the alpha 7-nAChR, but also alter receptor binding properties for its familiar ligands, including the alternative endogenous agonist choline. Of more long-term significance, these peptides also induce upregulation of alpha 7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane.Conclusions/Significance: The results reported here demonstrate a hitherto unknown relationship between the alpha 7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain. Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration.