TOK1 is a volatile anesthetic stimulated K+ channel.
BACKGROUND
Volatile anesthetic agents can activate the S channel, a baseline potassium (K+) channel, of the marine mollusk Aplysia. To investigate whether cloned ion channels with electrophysiologic properties similar to the S channel (potassium selectivity, outward rectification, and activation independent of voltage) also are modulated by volatile anesthetic agents, the authors expressed the cloned yeast ion channel TOK1 (tandem pore domain, outwardly rectifying K+ channel) in Xenopus oocytes and studied its sensitivity to volatile agents.


METHODS
Standard two-electrode voltage and patch clamp recording methods were used to study TOK1 channels expressed in Xenopus oocytes.


RESULTS
Studies with two-electrode voltage clamp at room temperature showed that halothane, isoflurane, and desflurane increased TOK1 outward currents by 48-65% in barium Frog Ringer's perfusate. The concentrations at which 50% potentiation occurred (EC50 values) were in the range of 768-814 microM (0.016-0.044 atm) and had a rank order of potency in atm in which halothane > isoflurane > desflurane. The potentiation of TOK1 by volatile anesthetic agents was rapid and reversible (onset and offset, 1-20 s). In contrast, the nonanesthetic 1,2-dichlorohexafluorocyclobutane did not potentiate TOK1 currents in concentrations up to five times the MAC value predicted by the Meyer-Overton hypothesis based on oil/gas partition coefficients. Single TOK1 channel currents were recorded from excised outside-out patches. The single channel open probability increased as much as twofold in the presence of isoflurane and rapidly returned to the baseline values on washout. Volatile anesthetic agents did not alter the TOK1 single channel current-voltage (I-V) relationship, however, suggesting that the site of action does not affect the permeation pathway of the channel.


CONCLUSIONS
TOK1 is a potassium channel that is stimulated by volatile anesthetic agents. The concentrations over which potentiation occurred (EC50 values) were higher than those commonly used in clinical practice (approximately twice MAC).
Gray
A T
AT
Department of Anesthesia, University of California School of Medicine, San Francisco, USA.
Winegar
B D
BD
Leonoudakis
D J
DJ
Forsayeth
J R
JR
Yost
C S
CS
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000077335:Desflurane; D004357:Drug Synergism; D004594:Electrophysiology; D006221:Halothane / Q000494:pharmacology; D007530:Isoflurane / Q000031:analogs & derivatives / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins; D014982:Xenopus laevis
D018685:Anesthetics, Inhalation; D015221:Potassium Channels; D029701:Saccharomyces cerevisiae Proteins; C095220:TOK1 protein, S cerevisiae; D000077335:Desflurane; D007530:Isoflurane; D006221:Halothane