Title | Isoflurane inhibits NaChBac, a prokaryotic voltage-gated sodium channel. |
Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Ouyang W, Jih T-Y, Zhang T-T, Correa AM, Hemmings HC |
Journal | J Pharmacol Exp Ther |
Volume | 322 |
Issue | 3 |
Pagination | 1076-83 |
Date Published | 2007 Sep |
ISSN | 0022-3565 |
Keywords | Anesthetics, Inhalation, Bacillus, Bacterial Proteins, Cell Line, Electrophysiology, Humans, Inhibitory Concentration 50, Ion Channel Gating, Isoflurane, Patch-Clamp Techniques, Sodium Channels, Transfection |
Abstract | 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 (IC(50) = 0.35 mM) than from -100 mV (IC(50) = 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. |
DOI | 10.1124/jpet.107.122929 |
Alternate Journal | J. Pharmacol. Exp. Ther. |
PubMed ID | 17569823 |
Grant List | GM58055 / GM / NIGMS NIH HHS / United States GM68044 / GM / NIGMS NIH HHS / United States R01 GM058055 / GM / NIGMS NIH HHS / United States |