Department of Anesthesiology

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Differential Inhibition of Neuronal Sodium Channel Subtypes by the General Anesthetic Isoflurane.

TitleDifferential Inhibition of Neuronal Sodium Channel Subtypes by the General Anesthetic Isoflurane.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhou C, Johnson KW, Herold KF, Hemmings HC
JournalJ Pharmacol Exp Ther
Date Published2019 Feb 21
ISSN1521-0103
Abstract

Volatile anesthetics depress neurotransmitter release in a brain region- and neurotransmitter-selective manner by unclear mechanisms. Voltage-gated sodium channels (Na), which are coupled to synaptic vesicle exocytosis, are inhibited by volatile anesthetics through reduction of peak current and modulation of gating. Subtype-selective effects of anesthetics on Na might contribute to observed neurotransmitter-selective anesthetic effects on release. We analyzed anesthetic effects on Na currents mediated by the principal neuronal Nav subtypes Na1.1, Na1.2 and Na1.6 heterologously expressed in ND7/23 neuroblastoma cells using whole-cell patch clamp electrophysiology. Isoflurane at clinically relevant concentrations induced a hyperpolarizing shift in the voltage-dependence of steady-state inactivation and slowed recovery from fast inactivation in all three Na subtypes, with the voltage of half-maximal steady-state inactivation significantly more positive for Na1.1 (-49.7±3.9 mV) than for Na1.2 (-57.5±1.2 mV) or Na1.6 (-58.0±3.8 mV). Isoflurane significantly inhibited peak Na current () in a voltage-dependent manner: at a physiologically relevant holding potential (V) of -70 mV, isoflurane inhibited peak of Na1.2 (16.5±5.5%) and Na1.6 (18.0±7.8%), but not of Na1.1 (1.2±0.8%). Since Na subtypes are differentially expressed both between neuronal types and within neurons, greater inhibition of Na1.2 and Na1.6 compared to Na1.1 could contribute to neurotransmitter-selective effects of isoflurane on synaptic transmission.

DOI10.1124/jpet.118.254938
Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID30792243