Department of Anesthesiology

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The general anesthetic isoflurane depresses synaptic vesicle exocytosis.

TitleThe general anesthetic isoflurane depresses synaptic vesicle exocytosis.
Publication TypeJournal Article
Year of Publication2005
AuthorsHemmings HC, Yan W, Westphalen RI, Ryan TA
JournalMol Pharmacol
Volume67
Issue5
Pagination1591-9
Date Published2005 May
ISSN0026-895X
KeywordsAnesthetics, General, Anesthetics, Inhalation, Animals, Cells, Cultured, Exocytosis, Hippocampus, Isoflurane, Rats, Rats, Sprague-Dawley, Synaptic Vesicles
Abstract

General anesthetics have marked effects on synaptic transmission, but the mechanisms of their presynaptic actions are unclear. We used quantitative laser-scanning fluorescence microscopy to analyze the effects of the volatile anesthetic isoflurane on synaptic vesicle cycling in cultured neonatal rat hippocampal neurons monitored using either transfection of a pH-sensitive form of green fluorescent protein fused to the luminal domain of VAMP (vesicle-associated membrane protein), (synapto-pHluorin) or vesicle loading with the fluorescent dye FM 1-43. Isoflurane reversibly inhibited action potential-evoked exocytosis over a range of concentrations, with little effect on vesicle pool size. In contrast, exocytosis evoked by depolarization in response to an elevated extracellular concentration of KCl, which is insensitive to the selective Na+ channel blocker tetrodotoxin, was relatively insensitive to isoflurane. Inhibition of exocytosis by isoflurane was resistant to bicuculline, indicating that this presynaptic effect is not caused by the well known GABA(A) receptor modulation by volatile anesthetics. Depression of exocytosis was mimicked by a reduction in stimulus frequency, suggesting a reduction in action potential initiation, conduction, or coupling to Ca2+ channel activation. There was no evidence for a direct effect on endocytosis. The effects of isoflurane on synaptic transmission are thus caused primarily by inhibition of action potential-evoked synaptic vesicle exocytosis at a site upstream of Ca2+ entry and exocytosis, possibly as a result of Na+ channel blockade and/or K+ channel activation, with the possibility of lesser contributions from Ca2+ channel blockade and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated vesicle fusion.

DOI10.1124/mol.104.003210
Alternate JournalMol. Pharmacol.
PubMed ID15728262
Grant ListGM58055 / GM / NIGMS NIH HHS / United States
GM61925 / GM / NIGMS NIH HHS / United States
P01 GM061925 / GM / NIGMS NIH HHS / United States