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NEUROPHARMACOLOGY

Effects of Alcohols and Anesthetics on Recombinant Voltage-Gated Na⁺ Channels

Waggoner Center for Alcohol and Addiction Research and the Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas

Voltage-gated Na⁺ channels (Na⁺ channels) mediate the rising phase of action potentials in neurons and excitable cells. Nine subtypes of the subunit (Na_v1.1-Na_v1.9) have been shown to form functional Na⁺ channels to date. Recently, anesthetic concentrations of volatile anesthetics and ethanol were reported to inhibit Na⁺ channel functions, but it is not known whether all subtypes are inhibited by anesthetics. To investigate possible subtype-specific effects of anesthetics on Na⁺ channels, mRNA of Na_v1.2, Na_v1.4, Na_v1.6, and Na_v1.8 subunit-encoded genes were injected individually or together with a subunit mRNA into Xenopus oocytes. Na⁺ currents were recorded using the two-electrode voltage-clamp technique. Isoflurane, at clinically relevant concentrations, inhibited the currents produced by Na_v1.2, Na_v1.4, and Na_v1.6 by 10% at the holding potential of -90 mV and by 30% at -60 mV, but it did not affect the Na_v1.8-mediated current. An anesthetic fluorocyclobutane (1-chloro-1,2,2-trifluorocyclobutane) also inhibited the Na_v1.2 channel, whereas the nonanesthetic fluorocyclobutane (1,2-dichlorohexafluorocyclobutane) had no effect. The perfluorinated heptanol [CF₃(CF₂)₅CH₂OH], which produces anesthesia, inhibited the Na_v1.2 channel like other alcohols tested (ethanol, heptanol, and CF₃CH₂OH), even though this compound does not affect GABA, glycine, -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, or kainate receptors. In contrast, most intravenous anesthetics did not have significant effects on the Na_v1.2 channel at clinically relevant concentrations although urethane inhibited. These results show that isoflurane inhibits the Na⁺ channel functions except Na_v1.8 in a voltage-dependent manner. These findings indicate that the Na⁺ channel is a neuronal target for anesthetic action.

Address correspondence to: Dr. R. Adron Harris, Waggoner Center for Alcohol and Addiction Research, 1 University Station A4800, University of Texas at Austin, Austin, TX 78712-0159. E-mail: harris{at}mail.utexas.edu

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