Transition states of voltage-gated sodium channels. At rest, the activation gate is closed and the channel is in a nonconducting state. After sufficient depolarization of the membrane, the channel undergoes a conformational change to enter the activated state where both gates are open, allowing the conduction of Na⁺ ions. After transitioning to the activated state, the channel undergoes fast inactivation, where intracellular residues (the inactivation gate) occlude the inside face of the channel blocking further conduction of Na⁺ ions. After recovery from inactivation, the channel returns to the resting state.

Schematic of the eukaryotic VGSC α-subunit. Roman numerals and numbers indicate domains and segments, respectively. The pore loop regions comprised of segments S5 and S6 are highlighted in green. Voltage-sensing S4 segments are highlighted in red. The inactivation gate and “h” particle containing the IFMT motif that is crucial for inactivation are highlighted in yellow. Small white circles of the re-entrant loops in each domain represent the amino acid residues that form the Na⁺ ion selectivity filter.

The halogenated ethers show differential inhibition of whole-cell Na⁺ current in Chinese hamster ovary cells expressing rat Na_v1.4 at 1 MAC. (A) Halothane; (B) isoflurane; (C) sevoflurane; (D) enflurane; (E) desflurane. Currents were evoked via 25-ms depolarizing pulses from a holding potential of −80 to −20 or −10 mV. Reproduced with permission from Ouyang et al. (2009).

Comparing the eukaryotic and prokaryotic VGSC structures. (Left) Two-dimensional schematic of the eukaryotic VGSC α-subunit. (Right) Two-dimensional schematic of NaChBac, the prokaryotic VGSC α-subunit found in Bacillus halodurans.

Basic overview of voltage-gated Na⁺ channels in synaptic transmission. (1) At rest, presynaptic voltage-gated Na⁺ and Ca²⁺ channels are closed. (2) Voltage-gated Na⁺ channels open, driving membrane depolarization and action potential propagation. (3) Voltage-gated Ca²⁺ channels open, raising intracellular levels of Ca²⁺. (4) Elevated intracellular Ca²⁺ triggers exocytosis. (5) Neurotransmitters are released into the synaptic cleft, activating postsynaptic receptors leading to a depolarization of the postsynaptic membrane. Due to the instrumental role voltage-gated Na⁺ channels play in this process, their inhibition by the halogenated ethers is likely to lead to dysfunction in neurotransmitter release.