Department of Anesthesiology

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Volatile anesthetics inhibit sodium channels without altering bulk lipid bilayer properties.

TitleVolatile anesthetics inhibit sodium channels without altering bulk lipid bilayer properties.
Publication TypeJournal Article
Year of Publication2014
AuthorsHerold KF, R Sanford L, Lee W, Schultz MF, Ingólfsson HI, Andersen OS, Hemmings HC
JournalJ Gen Physiol
Volume144
Issue6
Pagination545-60
Date Published2014 Dec
ISSN1540-7748
KeywordsAnesthetics, Inhalation, Animals, Cell Line, Dose-Response Relationship, Drug, Fluorobenzenes, Ion Channel Gating, Isoflurane, Lipid Bilayers, Mice, Neurons, Sodium, Sodium Channel Blockers, Volatile Organic Compounds, Voltage-Gated Sodium Channels
Abstract

Although general anesthetics are clinically important and widely used, their molecular mechanisms of action remain poorly understood. Volatile anesthetics such as isoflurane (ISO) are thought to alter neuronal function by depressing excitatory and facilitating inhibitory neurotransmission through direct interactions with specific protein targets, including voltage-gated sodium channels (Na(v)). Many anesthetics alter lipid bilayer properties, suggesting that ion channel function might also be altered indirectly through effects on the lipid bilayer. We compared the effects of ISO and of a series of fluorobenzene (FB) model volatile anesthetics on Na(v) function and lipid bilayer properties. We examined the effects of these agents on Na(v) in neuronal cells using whole-cell electrophysiology, and on lipid bilayer properties using a gramicidin-based fluorescence assay, which is a functional assay for detecting changes in lipid bilayer properties sensed by a bilayer-spanning ion channel. At clinically relevant concentrations (defined by the minimum alveolar concentration), both the FBs and ISO produced prepulse-dependent inhibition of Na(v) and shifted the voltage dependence of inactivation toward more hyperpolarized potentials without affecting lipid bilayer properties, as sensed by gramicidin channels. Only at supra-anesthetic (toxic) concentrations did ISO alter lipid bilayer properties. These results suggest that clinically relevant concentrations of volatile anesthetics alter Na(v) function through direct interactions with the channel protein with little, if any, contribution from changes in bulk lipid bilayer properties. Our findings further suggest that changes in lipid bilayer properties are not involved in clinical anesthesia.

DOI10.1085/jgp.201411172
Alternate JournalJ. Gen. Physiol.
PubMed ID25385786
PubMed Central IDPMC4242807
Grant ListGM021347 / GM / NIGMS NIH HHS / United States
GM058055 / GM / NIGMS NIH HHS / United States
R01 GM021342 / GM / NIGMS NIH HHS / United States