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This Article Full Text Full Text (PDF) All Versions of this Article: 102/2/1265    most recent 00252.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Herring, B. E. Articles by Fox, A. P. PubMed PubMed Citation Articles by Herring, B. E. Articles by Fox, A. P.

Isoflurane Inhibits the Neurotransmitter Release Machinery

¹Departments of Neurobiology, Pharmacology and Physiology, ²Anesthesia and Critical Care, and ³Pediatrics, University of Chicago, Chicago, Illinois

Submitted 20 March 2009; accepted in final form 3 June 2009

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 [Ca²⁺]_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.