Abstract
Volatile anesthetics depress neurotransmitter release in a brain region- and neurotransmitter-selective manner by unclear mechanisms. Voltage-gated sodium channels (Nav), 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 (Vh) of −70 mV, isoflurane inhibited peak INa 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 to Nav1.1 could contribute to neurotransmitter-selective effects of isoflurane on synaptic transmission.
- anesthesia
- anesthetics
- electrophysiology
- gases/general anesthetics
- patch clamp
- voltage gated channels
- voltage-gated sodium channels
- The American Society for Pharmacology and Experimental Therapeutics