The Two Different Effects of the Potential Neuroprotective Compound Minocycline on AMPA-Type Glutamate Receptors
The Two Different Effects of the Potential Neuroprotective Compound Minocycline on AMPA-Type Glutamate Receptors
复制标题
潜在神经保护化合物米诺环素对 AMPA 型谷氨酸受体的两种不同作用
DOI：
10.1159/000336773
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发表时间：
2012-01-01
期刊：
影响因子：
3.1
通讯作者：
Nie, Zhi-Yu
中科院分区：
文献类型：
--
作者：
Jin, Ling-Jing;Schlesinger, Friedrich;Nie, Zhi-Yu
背景：米诺环素在实验性神经退行性疾病中显示出神经保护作用。本研究的目的是探讨米诺环素与AMPA型受体通道之间是否存在直接的相互作用，并阐明其潜在的分子药理学机制。方法：采用膜片钳技术结合超快溶液交换系统研究米诺环素与重组AMPA型谷氨酸受体通道(同源GluR2flipGQ或非脱敏GluR2L504Y)的相互作用。结果：在与GluR2L504Y受体共同作用的实验中，细胞的相对峰值电流幅度(RAMP)和相对稳态电流(RCDES)呈剂量依赖性降低，而预先孵育实验中则无明显变化。此外，1或3 mm ol/L米诺环素可使电流衰减的快时间常数减小，并可观察到重开电流。而在GluR2flipGQ受体作用下，RAMP、曲线下相对面积和rCDES随米诺环素浓度的增加而增大，以3µm o l/L谷氨酸为激动剂时，稳态时间常数也增大。结论：米诺环素对AMPA型受体通道具有较弱的开放通道阻断作用和较强的增强作用，后者主要通过减弱受体的脱敏程度而起作用。
Background: Minocycline has demonstrated neuroprotective effects in experimental neurodegenerative diseases. The aim of this study was to investigate if there is any direct interaction between minocycline and the AMPA-type receptor channels, and to elucidate the underlying molecular pharmacological mechanisms. Methods: The patch-clamp technique was used combined with an ultrafast solution exchange system to investigate the interaction of minocycline with recombinant AMPA-type glutamate receptor channels (homomeric GluR2flipGQ or nondesensitizing GluR2L504Y). Results: Dose-dependent decreases in the relative peak current amplitude (rAmp) and the relative steady-state current (rCdes) were found in coapplication experiments with GluR2L504Y receptors, but not in preincubation experiments. Furthermore, coapplication of 1 or 3 mmol/l minocycline showed a decrease in the fast time constant of current decay, and reopening currents were observed. But in the test with GluR2flipGQ receptors, rAmp, relative area under the curve and rCdes increased with increasing concentrations of minocycline, and the steady-state time constant also increased when 3 µmol/l glutamate were used as agonist. Conclusion: Minocycline modulates AMPA-type receptor channels in a combination of a weaker open-channel block effect and a stronger potentiation effect, and the latter effect arises mainly from attenuating the extent of receptor desensitization.