TY - JOUR T1 - Effects of Alcohols and Anesthetics on Recombinant Voltage-Gated Na<sup>+</sup> Channels JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 987 LP - 994 DO - 10.1124/jpet.103.064063 VL - 309 IS - 3 AU - Munehiro Shiraishi AU - R. Adron Harris Y1 - 2004/06/01 UR - http://jpet.aspetjournals.org/content/309/3/987.abstract N2 - Voltage-gated Na+ channels (Na+ channels) mediate the rising phase of action potentials in neurons and excitable cells. Nine subtypes of the α subunit (Nav1.1-Nav1.9) 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 Nav1.2, Nav1.4, Nav1.6, and Nav1.8 α subunit-encoded genes were injected individually or together with a β 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 Nav1.2, Nav1.4, and Nav1.6 by ∼10% at the holding potential of -90 mV and by ∼30% at -60 mV, but it did not affect the Nav1.8-mediated current. An anesthetic fluorocyclobutane (1-chloro-1,2,2-trifluorocyclobutane) also inhibited the Nav1.2 channel, whereas the nonanesthetic fluorocyclobutane (1,2-dichlorohexafluorocyclobutane) had no effect. The perfluorinated heptanol [CF3(CF2)5CH2OH], which produces anesthesia, inhibited the Nav1.2 channel like other alcohols tested (ethanol, heptanol, and CF3CH2OH), even though this compound does not affect GABA, glycine, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, or kainate receptors. In contrast, most intravenous anesthetics did not have significant effects on the Nav1.2 channel at clinically relevant concentrations although urethane inhibited. These results show that isoflurane inhibits the Na+ channel functions except Nav1.8 in a voltage-dependent manner. These findings indicate that the Na+ channel is a neuronal target for anesthetic action. The American Society for Pharmacology and Experimental Therapeutics ER -