Inhibitory effects of ketamine and halothane on recombinant potassium channels from mammalian brain.
BACKGROUND
There is increasing evidence that direct interactions between volatile anesthetics and channel proteins may result in general anesthesia. Using voltage-clamp techniques, the authors examined the effect of two general anesthetics (ketamine and halothane) on a rat brain potassium channel of known amino acid sequence, and further assessed whether the inhibition of the channel is altered by a partial deletion of the C-terminal sequence of this channel.


METHODS
Xenopus laevis oocytes were microinjected with either Kv2.1 or delta C318 (a mutated channel in which the last 318 amino acids of the C-terminus have been deleted) cRNA, and channel function in translated channels was observed before, during, and after exposure to graded concentrations of ketamine (25, 50, and 75 micrometers) and halothane (1%, 2%, and 4%).


RESULTS
Ketamine and halothane reduced Kv2.1 and delta C318 peak current amplitude in a dose-dependent and reversible fashion. The inhibition of current was voltage dependent for halothane but not for ketamine. Halothane accelerated the time constant of current inactivation, whereas ketamine affected this parameter minimally in both channel types. Use dependence of ketamine and halothane action was observed in both Kv2.1 and the mutant channel, attributable to augmentation of C-type inactivation.


CONCLUSIONS
Although both ketamine and halothane inhibit potassium currents through the Kv2.1 channel, their mechanisms of action at this potential target may be different. Deletion of the C-terminal sequence resulted in decreased sensitivity to both anesthetics. Although it is not clear whether anesthetics interact directly with the C-terminus, which is thought to reside intracellularly, this portion of the channel protein clearly influences the actions of both anesthetics.
Kulkarni
R S
RS
Department of Anesthesiology, University of Massachusetts Medical Center, Worcester, USA.
Zorn
L J
LJ
Anantharam
V
V
Bayley
H
H
Treistman
S N
SN
D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014982:Xenopus laevis
D000778:Anesthetics, Dissociative; D018685:Anesthetics, Inhalation; D026902:Potassium Channel Blockers; D011994:Recombinant Proteins; D007649:Ketamine; D006221:Halothane