Inhibition of the human intermediate conductance Ca(2+)-activated K(+) channel, hIK1, by volatile anesthetics

Ca(2+)-activated K(+) channels (K(Ca)) regulate a wide variety of cellular functions by coupling intracellular Ca(2+) concentration to membrane potential. There are three major groups of K(Ca) classified by their unit conductances: large (BK), intermediate (IK), and small (SK) conductance of channels. BK channel is gated by combined influences of Ca(2+) and voltage, while IK and SK channels are gated solely by Ca(2+). Volatile anesthetics inhibit BK channel activity by interfering with the Ca(2+) gating mechanism. However, the effects of anesthetics on IK and SK channels are unknown. Using cloned IK and SK channels, hIK1 and hSK1-3, respectively, we found that the currents of hIK1 were inhibited rapidly and reversibly by volatile anesthetics, whereas those of SK channels were not affected. The IC(50) values of the volatile anesthetics, halothane, sevoflurane, enflurane, and isoflurane for hIK1 inhibition were 0.69, 0.42, 1.01 and 1.03 mM, respectively, and were in the clinically used concentration range. In contrast to BK channel, halothane inhibition of hIK1 currents was independent of Ca(2+) concentration, suggesting that Ca(2+) gating mechanism is not involved. These results demonstrate that volatile anesthetics, such as halothane, enflurane, isoflurane, and sevoflurane, affect BK, IK, and SK channels in distinct ways.