Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (I-K(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons
Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (I-K(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons
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DOI：
10.1111/j.1460-9568.1997.tb01637.x
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发表时间：
1997-03-01
影响因子：
3.4
通讯作者：
Brown, DA
中科院分区：
文献类型：
--
作者：
Lamas, JA;Selyanko, AA;Brown, DA
Linopirdine是一种认知增强剂，其增强皮层中去极化诱导的递质释放，并且正在考虑用于阿尔茨海默病的潜在治疗。先前已报道其抑制大鼠海马神经元的M型K+电流。在本实验中，我们已经测试了它对全细胞M-电流和单个M-通道，以及一系列其他膜电流，在分离的大鼠上级颈交感神经节细胞的影响。Linopirdine抑制全细胞M-电流的IC 50为3.4 μ M，并阻断M-通道记录在切除的外向膜补丁，但不在内外向补丁。这表明linopirdine直接从外部阻断M通道。它对抑制其他电压门控钾电流的有效性要低得多[延迟整流（I-K（V）），IC 50 63 μ M;瞬时（I-A）电流，IC 50 69 μ M]，并且在10-30 μ M时对快速和慢速Ca 2+激活的K+电流I-C和I-AHP或超极化激活的阳离子电流（I-Q/I-h）没有可检测到的抑制。然而，它减少乙酰胆碱激活的烟碱电流和GABA激活的Cl-电流，IC 50值分别为7.6和26 μ M。得出的结论是，利诺吡啶显示了一些20倍的选择性M-通道之间的不同的K+通道，但也可以阻止一些传输门控通道。本文还讨论了M通道阻滞与利诺吡啶中枢作用的关系。
Linopirdine is a cognition enhancer which augments depolarization-induced transmitter release in the cortex and which is under consideration for potential treatment of Alzheimer's disease. It has previously been reported to inhibit M-type K+ currents in rat hippocampal neurons. In the present experiments we have tested its effect on whole-cell M-currents and single M-channels, and on a range of other membrane currents, in dissociated rat superior cervical sympathetic ganglion cells. Linopirdine inhibited the whole-cell M-current with an IC50 of 3.4 mu M and blocked M-channels recorded in excised outside-out membrane patches but not in inside-out patches. This suggests that linopirdine directly blocks M-channels from the outside. It was much less effective in inhibiting other voltage-gated potassium currents [delayed rectifier (I-K(V)), IC50 63 mu M; transient (I-A) current, IC50 69 mu M] and produced no detectable inhibition of the fast and slow Ca2+-activated K+ currents I-C and I-AHP or of a hyperpolarization-activated cation current (I-Q/I-h) at 10-30 mu M. However, it reduced acetylcholine-activated nicotinic currents and GABA-activated Cl- currents with IC50 values of 7.6 and 26 mu M respectively. It is concluded that linopirdine shows some 20-fold selectivity for M-channels among different K+ channels but can also block some transmitter-gated channels. The relationship between M-channel block and the central actions of linopirdine are discussed.