Isoflurane inhibits the neurotransmitter release machinery

Despite their importance, the mechanism of action of general anesthetics is still poorly understood. Facilitation of inhibitory GABA(A) receptors plays an important role in anesthesia, but other targets have also been linked to anesthetic actions. Anesthetics are known to suppress excitatory synaptic transmission, but it has been difficult to determine whether they act on the neurotransmitter release machinery itself. By directly elevating [Ca(2+)](i) at neurotransmitter release sites without altering plasma membrane channels or receptors, we show that the commonly used inhalational general anesthetic, isoflurane, inhibits neurotransmitter release at clinically relevant concentrations, in a dose-dependent fashion in PC12 cells and hippocampal neurons. We hypothesized that a SNARE and/or SNARE-associated protein represents an important target(s) for isoflurane. Overexpression of a syntaxin 1A mutant, previously shown in Caenorhabditis elegans to block the behavioral effects of isoflurane, completely eliminated the reduction in neurotransmitter release produced by isoflurane, without affecting release itself, thereby establishing the possibility that syntaxin 1A is an intermediary in isoflurane's ability to inhibit neurotransmitter release.