Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons
Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons
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DOI：
10.1016/j.neuroscience.2008.06.009
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发表时间：
2008-08-13
期刊：
影响因子：
3.3
通讯作者：
Chen, H. -Z.
中科院分区：
文献类型：
--
作者：
Song, M. -K.;Liu, H.;Chen, H. -Z.
阻断特异性K+通道已被提出作为治疗神经退行性疾病的有前途的策略。利用计算机虚拟筛选方法和电生理测试，我们发现四种苦参碱是大鼠海马神经元延迟整流钾通道的有效阻断剂。本研究首先测定了四种生物碱对大鼠海马神经元电压门控性K ~+、Na ~+和Ca ~（2+）电流的作用，并确定了他拉替胺是延迟整流性K ~+通道的特异性阻断剂。体外应用他拉他敏可可逆地抑制延迟整流钾电流（I-K），其IC_（50）值为146.0 ± 5.8 μ M，并呈电压依赖性，但即使在1-3 mM的高浓度下，对电压门控Na ~+和Ca ~（2+）电流也有轻微的阻断作用。但不影响I-K通道的稳态失活和失活后的恢复，表明他拉替胺对I-K通道无变构作用，是一种与通道外孔入口结合的纯阻断剂。本研究首次从苦参生物碱中发现了有效的特异性I-K通道阻滞剂。通过阻断I-K通道抑制K+外流可能有助于阿尔茨海默病的治疗。因此，他拉他敏可以被认为是一个值得进一步研究的领先化合物。(C)2008年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Blocking specific K+ channels has been proposed as a promising strategy for the treatment of neurodegenerative diseases. Using a computational virtual screening approach and electrophysiological testing, we found four Aconitum alkaloids are potent blockers of the delayed rectifier K+ channel in rat hippocampal neurons. In the present study, we first tested the action of the four alkaloids on the voltagegated K+, Na+ and Ca2+ currents in rat hippocampal neurons, and then identified that talatisamine is a specific blocker for the delayed rectifier K+ channel. External application of talatisamine reversibly inhibited the delayed rectifier K+ current (I-K)with an IC50 value of 146.0 +/- 5.8 mu M in a voltage-dependent manner, but exhibited very slight blocking effect on the voltagegated Na+ and Ca2+ currents even at the high concentration of 1-3 mM. Moreover, talatisamine exerted a significant hyperpolarizing shift of the steady-state activation, but did not influence the steady state inactivation of I-K and its recovery from inactivation, suggesting that talatisamine had no allosteric action on I-K channel and was a pure blocker binding to the external pore entry of the channel. Our present study made the first discovery of potent and specific I-K channel blocker from Aconitum alkaloids. It has been argued that suppressing K+ efflux by blocking I-K channel may be favorable for Alzheimer's disease therapy. Talatisamine can therefore be considered as a leading compound worthy of further investigations. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.