Abstract
Neuronal voltage-gated sodium channels (Na(v)) are major targets for the neurophysiological actions of general anesthetics. In the adult brain, cell type-specific effects on synaptic transmission are attributed to the differential sensitivity to volatile anesthetics of specific Na(v) subtypes preferentially expressed in mature neurons (Na(v)1.1, Na(v)1.2, Na(v)1.6). Comparatively, developing neurons are more excitable than mature neurons. We determined volatile anesthetic effects on Na(+) currents mediated by Na(v)1.3, the principal Na(v) subtype expressed in developing neurons. Sevoflurane at clinical concentrations inhibited peak Na(+) current of human Na(v)1.3 heterologously expressed in HEK293T cells in a voltage-dependent manner, induced a - 6.1 mV hyperpolarizing shift in the voltage dependence of steady-state inactivation, and slowed recovery from fast inactivation. Na(v)1.3-mediated Na(+) currents also exhibited distinct activation properties associated with hyperexcitability, including prominent persistent currents and ramp currents, both of which were significantly reduced by sevoflurane. Na(v)1.3 showed a more depolarized voltage dependence of steady-state inactivation than Na(v)1.2, consistent with its higher propensity for sustained repetitive firing. Na(v)1.2 exhibited minimal persistent and ramp currents, and these were unaffected by sevoflurane. These findings identify subtype-specific effects of sevoflurane on neuronal Na(v) subtype electrophysiological properties, and suggest a mechanistic basis for increased anesthetic sensitivity and toxicity in early neuronal differentiation and maturation.