Blockade of the human ether-a-go-go-related gene potassium channel by ketamine.
OBJECTIVE
The inhibition of the cardiac rapid delayed rectifier potassium current (IKr ) and its cloned equivalent human ether-a-go-go-related gene (hERG) channel illustrate QT interval prolonging effects of a wide range of clinically used drugs. In this study, the direct interaction of the intravenous anaesthetic ketamine with wild-type (WT) and mutation hERG currents (IhERG ) was investigated.


METHODS
The hERG channel (WT, Y652A and F656A) was expressed in Xenopus oocytes and studied using standard two-microelectrode voltage-clamp techniques.


RESULTS
WT hERG is blocked in a concentration-dependent manner with IC50  = 12.05 ± 1.38 μm by ketamine, and the steady-state inactivation curves are shifted to more negative potentials (about -27 mV). The mutation to Ala of Y652 and F656 located on the S6 domain attenuate IhERG blockade by ketamine, and produced approximately 9-fold and 2.5-fold increases in IC50 compared with that of WT hERG channel, respectively.


CONCLUSIONS
Ketamine blocks WT IhERG expressed in Xenopus oocytes in a concentration-dependent manner and predominantly interacts with the open hERG channels. The interaction of ketamine with hERG channel may involve the aromatic residues Tyr652 and Phe656.
Cardio-Electrophysiological Research Laboratory, Medical College, Wuhan University of Science and Technology, Wuhan, China.
Peihua
P
Zhang
Junlian
J
Xing
Antao
A
Luo
Juan
J
Feng
Zhipei
Z
Liu
Chenghao
C
Gao
Jihua
J
Ma
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D007649:Ketamine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D014981:Xenopus
D000596:Amino Acids; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D007649:Ketamine
human ether-a-go-go-related gene; ketamine; potassium channels; voltage clamp techniques