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NEUROPHARMACOLOGY

Isoflurane Inhibits NaChBac, a Prokaryotic Voltage-Gated Sodium Channel

Departments of Anesthesiology (W.O., T.-Y.J., T.-T.Z., H.C.H.) and Pharmacology (H.C.H.), Weill Cornell Medical College, New York, New York; and Department of Pediatrics, Institute for Molecular Pediatric Sciences, University of Chicago, Chicago, Illinois (A.M.C.)

Volatile anesthetics inhibit mammalian voltage-gated Na⁺ channels, an action that contributes to their presynaptic inhibition of neurotransmitter release. We measured the effects of isoflurane, a prototypical halogenated ether volatile anesthetic, on the prokaryotic voltage-gated Na⁺ channel from Bacillus halodurans (NaChBac). Using whole-cell patch-clamp recording, human embryonic kidney 293 cells transfected with NaChBac displayed large inward currents (I_Na) that activated at potentials of –60 mV or higher with a peak voltage of activation of 0 mV (from a holding potential of –80 mV) or –10 mV (from a holding potential of –100 mV). Isoflurane inhibited I_Na in a concentration-dependent manner over a clinically relevant concentration range; inhibition was significantly more potent from a holding potential of –80 mV (IC₅₀ = 0.35 mM) than from –100 mV (IC₅₀ = 0.48 mM). Isoflurane positively shifted the voltage dependence of peak activation, and it negatively shifted the voltage dependence of end steady-state activation. The voltage dependence of inactivation was negatively shifted with no change in slope factor. Enhanced inactivation of I_Na was 8-fold more sensitive to isoflurane than reduction of channel opening. In addition to tonic block of closed and/or open channels, isoflurane enhanced use-dependent block by delaying recovery from inactivation. These results indicate that a prokaryotic voltage-gated Na⁺ channel, like mammalian voltage-gated Na⁺ channels, is inhibited by clinical concentrations of isoflurane involving multiple state-dependent mechanisms. NaChBac should provide a useful model for structure-function studies of volatile anesthetic actions on voltage-gated ion channels.

Address correspondence to: Dr. Hugh C. Hemmings, Weill Cornell Medical College, Box 50, LC-203, 525 E. 68th St., New York, NY 10065-4896. E-mail: hchemmi{at}med.cornell.edu