Salinska Elzbieta, Sobczuk Anna, Lazarewicz Jerzy W
Department of Neurochemistry, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland.
Neurosci Lett. 2008 Feb 20;432(2):137-40. doi: 10.1016/j.neulet.2007.12.013. Epub 2008 Jan 10.
In this study we tested the hypothesis that dantrolene, an established inhibitor of the skeletal muscle isoform of the ryanodine receptor, may interfere with activity of NMDA receptors in neurons. We assessed the effects of dantrolene on [(3)H]MK-801 and [(3)H]glycine binding to isolated rat cortical membranes. Dantrolene inhibited [(3)H]MK-801 binding in the presence of 100 microM NMDA with an IC(50) of 58.4 microM. The IC(50) value increased to 99.6, 343.0 and 364.6 microM in the presence of 10, 30 and 50 microM glycine, respectively, suggesting that dantrolene competes with glycine for binding site at the NMDA receptor complex. A binding assay using [(3)H]glycine confirmed this supposition: dantrolene inhibited strychnine-insensitive glycine binding in a dose-dependent way. Thus, our results show that dantrolene at concentrations of 50-100 microM and higher blocks the glycine binding site of the NMDA receptor complex and in this way inhibits activation of the NMDA ion channel. These data reveal a new mechanism of dantrolene action in neuronal tissue. Our results also suggest that the neuroprotective effect of dantrolene may be at least partly explained by its activity as a non-competitive antagonist of NMDA receptors.
在本研究中，我们检验了如下假设：丹曲林（一种已确定的兰尼碱受体骨骼肌亚型抑制剂）可能会干扰神经元中NMDA受体的活性。我们评估了丹曲林对[³H]MK-801和[³H]甘氨酸与分离的大鼠皮质膜结合的影响。在存在100微摩尔/升NMDA的情况下，丹曲林抑制[³H]MK-801结合，其半数抑制浓度（IC₅₀）为58.4微摩尔/升。在分别存在10、30和50微摩尔/升甘氨酸的情况下，IC₅₀值分别增至99.6、343.0和364.6微摩尔/升，这表明丹曲林与甘氨酸在NMDA受体复合物上竞争结合位点。一项使用[³H]甘氨酸的结合试验证实了这一推测：丹曲林以剂量依赖方式抑制士的宁不敏感的甘氨酸结合。因此，我们的结果表明，浓度为50 - 100微摩尔/升及更高的丹曲林会阻断NMDA受体复合物的甘氨酸结合位点，从而抑制NMDA离子通道的激活。这些数据揭示了丹曲林在神经组织中的一种新作用机制。我们的结果还表明，丹曲林的神经保护作用可能至少部分是由其作为NMDA受体非竞争性拮抗剂的活性所解释的。
