MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on February 22, 2005; DOI: 10.1124/mol.104.003210

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.104.003210v1
67/5/1591    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hemmings Jr, H. C
Right arrow Articles by Ryan, T. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hemmings Jr, H. C
Right arrow Articles by Ryan, T. A.


Received for publication July 26, 2004.
Revised February 15, 2005.
Accepted for publication February 22, 2005.

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

Hugh C Hemmings Jr 1*, Wayne Yan 1, Robert I. Westphalen 1, Timothy A. Ryan 1

1 Weill Cornell Medical College

* Address correspondence to: E-mail: hchemmi{at}med.cornell.edu

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 lumenal domain of VAMP (synapto-pHlourin) 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 due to the well-known GABAA 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 primarily due to inhibition of action potential-evoked synaptic vesicle exocytosis at a site upstream of Ca2+ entry and exocytosis, possibly due to Na+ channel blockade and/or K+ channel activation, with the possibility of lesser contributions from Ca2+ channel blockade and/or SNARE-mediated vesicle fusion.


Key words: Fluorescence techniques, Gases/general anesthetics, Exocytosis


This article has been cited by other articles:


Home page
 Br J AnaesthHome page
D. Fu, P. Vissavajjhala, and H. C. Hemmings Jr
Volatile anaesthetic effects on phospholipid binding to synaptotagmin 1, a presynaptic Ca2+ sensor
Br. J. Anaesth., August 1, 2005; 95(2): 216 - 221.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics