N-甲基-D-天冬氨酸受体开放通道阻滞剂对人α7烟碱型乙酰胆碱受体的抑制作用。
Inhibition of human alpha 7 nicotinic acetylcholine receptors by open channel blockers of N-methyl-D-aspartate receptors.
作者信息
Maskell Peter D, Speder Pauline, Newberry Nigel R, Bermudez Isabel
机构信息
School of Biological and Molecular Sciences, Oxford Brookes University, Oxford OX3 0BP.
出版信息
Br J Pharmacol. 2003 Dec;140(7):1313-9. doi: 10.1038/sj.bjp.0705559.
Abstract
- Human alpha 7 nicotinic acetylcholine (ACh) receptors were expressed in Xenopus oocytes and the effects of the N-methyl-D-aspartate (NMDA) receptor open channel blockers memantine and cerestat on this receptor were examined using two-electrode voltage-clamp recordings and 125I-alpha-bungarotoxin (125I-alpha-bgtx) binding. 2. Memantine and cerestat produced complete inhibition of ACh-induced inward currents with affinities similar to that reported for native NMDA receptors. Cerestat, IC50 1.7 (-1; +2) microm, was more potent than memantine, IC50 5 (-3;+8) microM, and the effects of both drugs were fully and rapidly reversible. 3. Inhibition of alpha 7 receptor function was voltage-independent, and it occurred at concentrations far lower than those needed to inhibit (never completely) binding of 125I-alpha-bgtx to alpha 7 receptors, suggesting that the effects of memantine or cerestat are noncompetitive. 4. These results provide evidence that human alpha 7 receptors are inhibited by memantine and cerestat and suggest that caution should be applied when using these compounds to study systems in which NMDA and nACh receptors co-exist.
摘要
- 将人α7烟碱型乙酰胆碱（ACh）受体在非洲爪蟾卵母细胞中表达，并用双电极电压钳记录法和125I-α-银环蛇毒素（125I-α-bgtx）结合法检测N-甲基-D-天冬氨酸（NMDA）受体开放通道阻滞剂美金刚和西瑞司他对该受体的影响。2. 美金刚和西瑞司他对ACh诱导的内向电流产生完全抑制，其亲和力与报道的天然NMDA受体相似。西瑞司他的IC50为1.7（-1；+2）微摩尔，比美金刚（IC50为5（-3；+8）微摩尔）更有效，且两种药物的作用均完全且迅速可逆。3. 对α7受体功能的抑制与电压无关，且发生时的浓度远低于抑制（从未完全抑制）125I-α-bgtx与α7受体结合所需的浓度，这表明美金刚或西瑞司他的作用是非竞争性的。4. 这些结果证明美金刚和西瑞司他可抑制人α7受体，并提示在使用这些化合物研究NMDA和nACh受体共存的系统时应谨慎。
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