Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons

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.