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

J Pharmacol Exp Ther. 2019 May;369(2):200-211. doi: 10.1124/jpet.118.254938. Epub 2019 Feb 21.

Abstract

Volatile anesthetics depress neurotransmitter release in a brain region- and neurotransmitter-selective manner by unclear mechanisms. Voltage-gated sodium channels (Navs), 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 Nav might contribute to observed neurotransmitter-selective anesthetic effects on release. We analyzed anesthetic effects on Na+ currents mediated by the principal neuronal Nav subtypes Nav1.1, Nav1.2, and Nav1.6 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 Nav subtypes, with the voltage of half-maximal steady-state inactivation significantly more positive for Nav1.1 (-49.7 ± 3.9 mV) than for Nav1.2 (-57.5 ± 1.2 mV) or Nav1.6 (-58.0 ± 3.8 mV). Isoflurane significantly inhibited peak Na+ current (I Na) in a voltage-dependent manner: at a physiologically relevant holding potential of -70 mV, isoflurane inhibited peak I Na of Nav1.2 (16.5% ± 5.5%) and Nav1.6 (18.0% ± 7.8%), but not of Nav1.1 (1.2% ± 0.8%). Since Nav subtypes are differentially expressed both between neuronal types and within neurons, greater inhibition of Nav1.2 and Nav1.6 compared with Nav1.1 could contribute to neurotransmitter-selective effects of isoflurane on synaptic transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, General / pharmacology*
  • Animals
  • Electrophysiological Phenomena / drug effects
  • Isoflurane / pharmacology*
  • Kinetics
  • Neurons / cytology*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurotransmitter Agents / metabolism
  • Synapses / drug effects
  • Synapses / physiology
  • Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

  • Anesthetics, General
  • Neurotransmitter Agents
  • Voltage-Gated Sodium Channel Blockers
  • Isoflurane