Effect of MK-801 at the human alpha 7 nicotinic acetylcholine receptor
Effect of MK-801 at the human alpha 7 nicotinic acetylcholine receptor
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DOI：
10.1016/0028-3908(96)00006-8
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发表时间：
1996-04-01
影响因子：
4.7
通讯作者：
McKenna, DG
中科院分区：
文献类型：
--
作者：
Briggs, CA;McKenna, DG
测定了非洲爪蟾卵母细胞中表达的人α 7烟碱乙酰胆碱受体（α 7 nAChR）在钡（10 mM）和阿托品（2 μ M）存在下的反应，钡（10 mM）可以阻止Ca2+依赖性Cl-电流的二次激活，阿托品（2 μ M）可以阻断内源性毒蕈碱受体。在不同的实验中，乙酰胆碱引起的EC（50）值为177+/-32 μ M ~ 272+/-26 μ M。nAChR拮抗剂α -班加罗毒素（IC50=0.54+/-0.04 nM）、甲基莱卡乌碱（IC50=0.64+/-0.08 nM）和甲胺（IC50=1.8+/-02 μ M）可抑制乙酰胆碱（200 μ M）的反应。此外，n-甲基- d -天冬氨酸（NMDA）敏感谷氨酸受体通道的非竞争性阻滞剂MK-801可抑制α - 7 nAChR。这种效应不是立体选择性的；（+）-MK-801的IC50为15+/-3 μ M， (-)-MK-801的IC50为14+/-3 μ M。与甲基茄碱不同，MK-801的抑制作用依赖于细胞电位，与通道阻断机制一致。MK-801的抑制作用逆转较慢（时间常数约为20 min），而甲基茄头碱的抑制作用在10 min内恢复100%。然而，MK-801似乎没有被困在通道中，因为抑制的恢复对刺激率或细胞电位的依赖性很小。因此，MK-801作为非立体选择性α - 7 nAChR抑制剂，其效力仅比nAChR拮抗剂甲胺低约8倍，可能通过通道阻断起作用。1996爱思唯尔科学有限公司
Responses of the human alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) expressed in Xenopus laevis oocytes were quantified in the presence of barium (10 mM) to prevent secondary activation of Ca2+-dependent Cl- currents and atropine (2 mu M) to block endogenous muscarinic receptors. Acetylcholine (ACh) elicited responses with EC(50) values of 177+/-32 mu M to 272+/-26 mu M in different experiments. Responses to ACh (200 mu M) were blocked by the nAChR antagonists alpha-bungarotoxin (IC50=0.54+/-0.04 nM), methyllycaconitine (IC50=0.64+/-0.08 nM) and mecamylamine (IC50=1.8+/-02 mu M) Additionally, MK-801, a non-competitive blocker of N-methyl-D-aspartate (NMDA) sensitive glutamate receptor channels, inhibited the human alpha 7 nAChR. This effect was not stereoselective; the IC50 for (+)-MK-801 was 15+/-3 mu M while that for (-)-MK-801 was 14+/-3 mu M The inhibition by MK-801, in contrast to methyllycaconitine, was dependent upon cell potential, consistent with a mechanism involving channel blockade. The inhibition by MK-801 reversed slowly (time constant approximately 20 min) compared to that by methyllycaconitine (100% recovery within 10 min). However, MK-801 did not appear to be trapped in the channel because the recovery from inhibition showed little dependence upon stimulation rate or cell potential. Thus, MK-801 acted as a non-stereoselective alpha 7 nAChR inhibitor that was only about 8-fold less potent than the nAChR antagonist mecamylamine and probably acted through channel blockade. (C) 1996 Elsevier Science Ltd.