X Li1, C Czajkowski, R A Pearce. 1. Department of Anesthesiology, University of Wisconsin, Madison, Wisconsin 53706, USA.
Abstract
BACKGROUND: Hypotheses regarding the nature of channel modulation by volatile anesthetics have focused primarily on "membrane actions" of anesthetics and more recently on direct actions of volatile agents on receptor proteins themselves. With the recognition that many channels are subject to modulation by intracellular enzymes, such as protein kinases and phosphatases, and recent demonstrations that the activity of these modulators themselves may be altered by anesthetic agents, a third possibility has been suggested:-anesthetic actions on channels may be indirect, produced, for example, via direct effects on intracellular enzyme systems. METHODS: To determine the contribution of indirect versus direct modulation, the authors compared effects of the volatile anesthetic halothane on gamma-aminobutyric acid A receptors under two conditions: in the whole cell configuration with intact intracellular regulatory systems, and in the excised patch configuration, in which intracellular signaling systems have been disrupted. They also evaluated the effects of rapid application and withdrawal of anesthetic to determine the time course of onset and offset of the anesthetic actions on these channels. RESULTS: Characteristic changes in gamma-aminobutyric acid A receptor function occurred in excised patches as in whole cells, did not require alteration of receptor phosphorylation, and were rapid (onset and offset of anesthetic action occurred within milliseconds). CONCLUSIONS: These results are not consistent with indirect modulation but rather indicate that volatile agents modulate gamma-aminobutyric acid A receptors by direct action on the channel complex or surrounding lipid membrane.
BACKGROUND: Hypotheses regarding the nature of channel modulation by volatile anesthetics have focused primarily on "membrane actions" of anesthetics and more recently on direct actions of volatile agents on receptor proteins themselves. With the recognition that many channels are subject to modulation by intracellular enzymes, such as protein kinases and phosphatases, and recent demonstrations that the activity of these modulators themselves may be altered by anesthetic agents, a third possibility has been suggested:-anesthetic actions on channels may be indirect, produced, for example, via direct effects on intracellular enzyme systems. METHODS: To determine the contribution of indirect versus direct modulation, the authors compared effects of the volatile anesthetic halothane on gamma-aminobutyric acid A receptors under two conditions: in the whole cell configuration with intact intracellular regulatory systems, and in the excised patch configuration, in which intracellular signaling systems have been disrupted. They also evaluated the effects of rapid application and withdrawal of anesthetic to determine the time course of onset and offset of the anesthetic actions on these channels. RESULTS: Characteristic changes in gamma-aminobutyric acid A receptor function occurred in excised patches as in whole cells, did not require alteration of receptor phosphorylation, and were rapid (onset and offset of anesthetic action occurred within milliseconds). CONCLUSIONS: These results are not consistent with indirect modulation but rather indicate that volatile agents modulate gamma-aminobutyric acid A receptors by direct action on the channel complex or surrounding lipid membrane.
Authors: Karen Krzywkowski; Paul A Davies; Paula L Feinberg-Zadek; Hans Bräuner-Osborne; Anders A Jensen Journal: Proc Natl Acad Sci U S A Date: 2008-01-09 Impact factor: 11.205