TOK1 IS A VOLATILE ANESTHETIC STIMULATED K+ CHANNEL

Background: Volatile anesthetic agents can activate the S channel, a b aseline potassium (K+) channel, of the marine mollusk Aplysia. To inve stigate whether cloned ion channels with electrophysiologic properties similar to the S channel (potassium selectivity, outward rectificatio n, and activation independent of voltage) also are modulated by volati le anesthetic agents, the authors expressed the cloned yeast ion chann el TOK1 (tandem pore domain, outwardly rectifying K+ channel) in Xenop us oocytes and studied its sensitivity to volatile agents. Methods: St andard two-electrode voltage and patch clamp recording methods were us ed to study TOK1 channels expressed in Xenopus oocytes. Results: Studi es with two-electrode voltage clamp at room temperature showed that ha lothane, 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 mu M (0.016-0.044 atm) and had a rank order of potency in atm in which halothane > isoflurane > desflurane. The potentiation of TOK1 by vola tile anesthetic agents was rapid and reversible (onset and offset, 1-2 0 s). Ln contrast, the non-anesthetic 1,2-dichlorohexafluorocyclobutan e did not potentiate TOK1 currents in concentrations up to five times the MAC value predicted by the Meyer-Overton hypothesis based on oil/g as 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 agent s did not alter the TOK1 single channel current-voltage (I-V) relation ship, however, suggesting that the site of action does not affect the permeation pathway of the channel Conclusion: TOK1 is a potassium chan nel that is stimulated by volatile anesthetic agents. The concentratio ns over which potentiation occurred (EC50 values) were higher than tho se commonly used in clinical practice (approximately twice MAC).