Sevoflurane inhibition of the developmentally expressed neuronal sodium channel Nav1.3

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_v1.1, Na_v1.2, Na_v1.6). Comparatively, developing neurons are more excitable than mature neurons. We determined volatile anesthetic effects on Na⁺ currents mediated by Na_v1.3, the principal Na_v subtype expressed in developing neurons. Sevoflurane at clinical concentrations inhibited peak Na⁺ current of human Na_v1.3 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_v1.3-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_v1.3 showed a more depolarized voltage dependence of steady-state inactivation than Na_v1.2, consistent with its higher propensity for sustained repetitive firing. Na_v1.2 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.