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 voltage-gated 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 (IK) with an IC50 value of 146.0+/-5.8 microM in a voltage-dependent manner, but exhibited very slight blocking effect on the voltage-gated 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 IK and its recovery from inactivation, suggesting that talatisamine had no allosteric action on IK 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 IK channel blocker from Aconitum alkaloids. It has been argued that suppressing K+ efflux by blocking IK channel may be favorable for Alzheimer's disease therapy. Talatisamine can therefore be considered as a leading compound worthy of further investigations.
Song
M-K
MK
Department of Pharmacology, Institute of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, 280 South Chongqing Road, Shanghai 200025, PR China.
Liu
H
H
Jiang
H-L
HL
Yue
J-M
JM
Hu
G-Y
GY
Chen
H-Z
HZ
D000157:Aconitine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000502:physiology
C114773:14-benzoyltalitasamine; D000470:Alkaloids; D015220:Calcium Channels; D051668:Delayed Rectifier Potassium Channels; D004365:Drugs, Chinese Herbal; D026902:Potassium Channel Blockers; D015222:Sodium Channels; C069834:talatisamine; C057217:songorine; D000157:Aconitine