The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis
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...
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Published in | Molecular pharmacology Vol. 67; no. 5; pp. 1591 - 1599 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.05.2005
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Subjects | |
Online Access | Get full text |
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Summary: | 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 1â43. 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 Ca 2+ 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 Ca 2+ entry and exocytosis, possibly as a result of Na + channel blockade and/or K + channel activation, with the possibility of lesser contributions from Ca 2+ channel blockade and/or soluble N -ethylmaleimide-sensitive factor attachment protein receptor-mediated vesicle fusion. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.104.003210 |