Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 322, Issue 3, Pages 1076-1083Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.107.122929
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- NIGMS NIH HHS [GM68044, GM58055, R01 GM058055] Funding Source: Medline
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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.
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