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

The Journal of Pharmacology and Experimental Therapeutics
Cheng ZhouHugh C Hemmings

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 (INa) in a voltage-dependent manner: at a physiologically relevant holding potential of -70 mV, isoflurane inhibited peak INa of Nav1...Continue Reading

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Sep 1, 2019·Pharmacological Reviews·Nicholas DenommeGeorge A Mashour
Jul 9, 2020·Frontiers in Cellular Neuroscience·Rainer Viktor HaberbergerDusan Matusica
Feb 29, 2020·Current Neuropharmacology·Xuechao HaoCheng Zhou

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