Webb C P, Nedergaard S, Giles K, Greenfield S A
University Department of Pharmacology, Oxford, UK.
Eur J Neurosci. 1996 Apr;8(4):837-41. doi: 10.1111/j.1460-9568.1996.tb01270.x.
Evidence is accumulating that a soluble, secretory form of acetylcholinesterase may have novel, non-cholinergic functions in certain brain regions, such as the substantia nigra. In this study, application of human recombinant acetylcholinesterase (rhAChE) to pars compacta neurons in the rostral substantia nigra resulted in a sustained hyperpolarization that was not only mimicked by application of N-methyl-D-aspartate (NMDA) but also blocked by the NMDA receptor antagonists MK8O1 and 2-amino-5-phosphonopentanoic acid. Neither the rhAChE- nor the NMDA-induced hyperpolarization was seen when the calcium chelator BAPTA was injected into the neuron; hence the effect is mediated by accumulation of intracellular calcium. This intracellular calcium appears sufficient to compromise neuronal metabolism since the rhAChE-induced hyperpolarization was reversed by application of the K-ATP channel antagonist tolbutamide. Butyrylcholinesterase, a protein of similar molecular weight to acetylcholinesterase, which also hydrolyses acetylcholine, had no effect whatsoever. The results suggest that, independent of its normal catalytic function, acetylcholinesterase can act via the NMDA receptor complex to enhance calcium entry into nigral neurons and jeopardize cell metabolism. This non-classical action of acetylcholinesterase might thus be an important factor in the mechanisms underlying parkinsonian neurodegeneration.
越来越多的证据表明，可溶性分泌形式的乙酰胆碱酯酶在某些脑区，如黑质，可能具有新的非胆碱能功能。在本研究中，将人重组乙酰胆碱酯酶（rhAChE）应用于黑质前部致密部的神经元，导致持续的超极化，这种超极化不仅可被N-甲基-D-天冬氨酸（NMDA）模拟，还可被NMDA受体拮抗剂MK801和2-氨基-5-膦酸戊酸阻断。当向神经元中注射钙螯合剂BAPTA时，未观察到rhAChE或NMDA诱导的超极化；因此，这种效应是由细胞内钙的积累介导的。这种细胞内钙似乎足以损害神经元代谢，因为rhAChE诱导的超极化可被K-ATP通道拮抗剂甲苯磺丁脲逆转。丁酰胆碱酯酶是一种分子量与乙酰胆碱酯酶相似的蛋白质（也可水解乙酰胆碱），但没有任何作用。结果表明，乙酰胆碱酯酶与其正常催化功能无关，可通过NMDA受体复合物作用，增强钙进入黑质神经元并危及细胞代谢。因此，乙酰胆碱酯酶的这种非经典作用可能是帕金森病神经退行性变机制中的一个重要因素。
