Shaker-Related Potassium Channels in the Central Medial Nucleus of the Thalamus Are Important Molecular Targets for Arousal Suppression by Volatile General Anesthetics

Background Although it is accepted widely that optically active intravenous general anesthetics produce stereoselective effects in animals, the situation regarding volatile agents is confused. Conventional studies with scarce isoflurane enantiomers have been limited to small numbers of animals and produced conflicting results. By injecting these volatile enantiomers intravenously, however, it is possible to study large numbers of animals and obtain reliable results that can help to identify the molecular targets for isoflurane. Methods Pure isoflurane enantiomers were administered intravenously to rats after solubilization in a lipid emulsion. The ability of each enantiomer to produce a loss of righting reflex was determined as a function of dose, and quantal dose-response curves were constructed. In addition, sleep times were recorded with each enantiomer. Chiral gas chromatography was used to measure relative enantiomer concentrations in the brains of rats injected with racemic isoflurane. Results The S(+)-enantiomer was 40 +/- 8% more potent than the R(-)-enantiomer at producing a loss of righting reflex. The S(+)-enantiomer induced longer sleep times (by about 50%) than did the R(-)-enantiomer. Rats anesthetized by a dose of racemic isoflurane sufficient to achieve a half-maximal effect had essentially identical brain concentrations of the two enantiomers. Conclusions The S(+)-enantiomer of the general anesthetic isoflurane is significantly (P < 0.001) more potent than the R(-)-enantiomer at causing a loss of righting reflex in rats. This confirms the view that isoflurane acts by binding to chiral sites. The observed degree of stereoselectivity provides a useful guide for ascertaining from in vitro experiments which molecular targets are most likely to play major roles in the loss of righting reflex caused by isoflurane.

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Fluorinated General Anesthetics Modulate Kv1.3 Potassium Channels and Interact With β-Amyloid Peptide: Is there a Link?

Biophysical Journal ◽

10.1016/j.bpj.2009.12.2899 ◽

2010 ◽

Vol 98 (3) ◽

pp. 534a

Author(s):

Maria I. Lioudyno ◽

Michael T. Alkire ◽

Virginia Liu ◽

Philip R. Dennison ◽

Charles G. Glabe ◽

...

Keyword(s):

Potassium Channels ◽

Amyloid Peptide ◽

General Anesthetics ◽

Β Amyloid ◽

Β Amyloid Peptide

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The Effects of General Anesthetics on Synaptic Transmission

Current Neuropharmacology ◽

10.2174/1570159x18666200227125854 ◽

2020 ◽

Vol 18 (10) ◽

pp. 936-965

Author(s):

Xuechao Hao ◽

Mengchan Ou ◽

Donghang Zhang ◽

Wenling Zhao ◽

Yaoxin Yang ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Ion Channels ◽

Side Effects ◽

Synaptic Transmission ◽

Molecular Targets ◽

Synaptic Function ◽

General Anesthetics ◽

Voltage Gated ◽

The Central Nervous System

General anesthetics are a class of drugs that target the central nervous system and are widely used for various medical procedures. General anesthetics produce many behavioral changes required for clinical intervention, including amnesia, hypnosis, analgesia, and immobility; while they may also induce side effects like respiration and cardiovascular depressions. Understanding the mechanism of general anesthesia is essential for the development of selective general anesthetics which can preserve wanted pharmacological actions and exclude the side effects and underlying neural toxicities. However, the exact mechanism of how general anesthetics work is still elusive. Various molecular targets have been identified as specific targets for general anesthetics. Among these molecular targets, ion channels are the most principal category, including ligand-gated ionotropic receptors like γ-aminobutyric acid, glutamate and acetylcholine receptors, voltage-gated ion channels like voltage-gated sodium channel, calcium channel and potassium channels, and some second massager coupled channels. For neural functions of the central nervous system, synaptic transmission is the main procedure for which information is transmitted between neurons through brain regions, and intact synaptic function is fundamentally important for almost all the nervous functions, including consciousness, memory, and cognition. Therefore, it is important to understand the effects of general anesthetics on synaptic transmission via modulations of specific ion channels and relevant molecular targets, which can lead to the development of safer general anesthetics with selective actions. The present review will summarize the effects of various general anesthetics on synaptic transmissions and plasticity.

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Molecular Targets of General Anesthetics in the Nervous System

Suppressing the Mind ◽

10.1007/978-1-60761-462-3_2 ◽

2009 ◽

pp. 11-31 ◽

Cited By ~ 1

Author(s):

Hugh C. Hemmings

Keyword(s):

Nervous System ◽

Molecular Targets ◽

General Anesthetics

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Differential Effects of General Anesthetics on G Protein–coupled Inwardly Rectifying and Other Potassium Channels

Anesthesiology ◽

10.1097/00000542-200107000-00025 ◽

2001 ◽

Vol 95 (1) ◽

pp. 144-153 ◽

Cited By ~ 45

Author(s):

Tomohiro Yamakura ◽

Joanne M. Lewohl ◽

R. Adron Harris

Keyword(s):

Nitrous Oxide ◽

Potassium Channels ◽

G Protein ◽

Volatile Anesthetics ◽

General Anesthetics ◽

Girk Channels ◽

Intravenous Anesthetics ◽

Amino Acid Mutations ◽

Inwardly Rectifying ◽

G Protein Coupled

Background General anesthetics differentially affect various families of potassium channels, and some potassium channels are suggested to be potential targets for anesthetics and alcohols. Methods The voltage-gated (ERG1, ELK1, and KCNQ2/3) and inwardly rectifying (GIRK1/2, GIRK1/4, GIRK2, IRK1, and ROMK1) potassium channels were expressed in Xenopus oocytes. Effects of volatile agents [halothane, isoflurane, enflurane, F3 (1-chloro-1,2,2-trifluorocyclobutane), and the structurally related nonimmobilizer F6 (1,2-dichlorohexafluorocyclobutane)], as well as intravenous (pentobarbital, propofol, etomidate, alphaxalone, ketamine), and gaseous (nitrous oxide) anesthetics and alcohols (ethanol and hexanol) on channel function were studied using a two-electrode voltage clamp. Results ERG1, ELK1, and KCNQ2/3 channels were either inhibited slightly or unaffected by concentrations corresponding to twice the minimum alveolar concentrations or twice the anesthetic EC50 of volatile and intravenous anesthetics and alcohols. In contrast, G protein-coupled inwardly rectifying potassium (GIRK) channels were inhibited by volatile anesthetics but not by intravenous anesthetics. The neuronal-type GIRK1/2 channels were inhibited by 2 minimum alveolar concentrations of halothane or F3 by 45 and 81%, respectively, whereas the cardiac-type GIRK1/4 channels were inhibited only by F3. Conversely, IRK1 and ROMK1 channels were completely resistant to all anesthetics tested. Current responses of GIRK2 channels activated by mu-opioid receptors were also inhibited by halothane. Nitrous oxide (approximately 0.6 atmosphere) slightly but selectively potentiated GIRK channels. Results of chimeric and multiple amino acid mutations suggest that the region containing the transmembrane domains, but not the pore-forming domain, may be involved in determining differences in anesthetic sensitivity between GIRK and IRK channels. Conclusions G protein-coupled inwardly rectifying potassium channels, especially those composed of GIRK2 subunits, were inhibited by clinical concentrations of volatile anesthetics. This action may be related to some side effects of these agents.

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Volatile General Anesthetics Produce Hyperpolarization of Aplysia Neurons by Activation of a Discrete Population of Baseline Potassium Channels

Anesthesiology ◽

10.1097/00000542-199610000-00026 ◽

1996 ◽

Vol 85 (4) ◽

pp. 889-900 ◽

Cited By ~ 33

Author(s):

Bruce D. Winegar ◽

David F. Owen ◽

Spencer C. Yost ◽

John R. Forsayeth ◽

Earl Mayeri

Keyword(s):

Potassium Channels ◽

Neuronal Excitability ◽

Single Channel ◽

Volatile Anesthetics ◽

Specific Class ◽

General Anesthetics ◽

Open Probability ◽

Discrete Population ◽

Linear Slope ◽

Ganglion Neurons

Background The mechanism by which volatile anesthetics act on neuronal tissue to produce reversible depression is unknown. Previous studies have identified a potassium current in invertebrate neurons that is activated by volatile anesthetics. The molecular components generating this current are characterized here in greater detail. Methods The cellular and biophysical effects of halothane and isoflurane on neurons of Aplysia californica were studied. Isolated abdominal ganglia were perfused with anesthetic-containing solutions while membrane voltage changes were recorded. These effects were also studied at the single-channel level by patch clamping cultured neurons from the abdominal and pleural ganglia. Results Clinically relevant concentrations of halothane and isoflurane produced a slow hyperpolarization in abdominal ganglion neurons that was sufficient to block spontaneous spike firings. Single-channel studies revealed specific activation by volatile anesthetics of a previously described potassium channel. In pleural sensory neurons, halothane and isoflurane increased the open probability of the outwardly rectifying serotonin-sensitive channel (S channel). Halothane also inhibited a smaller noninactivating channel with a linear slope conductance of approximately 40 pS. S channels were activated by halothane with a median effective concentration of approximately 500 microM (0.013 atm), which increased channel activity about four times. The mechanism of channel activation involved shortening the closed-time durations between bursts and apparent recruitment of previously silent channels. Conclusions The results demonstrate a unique ability of halothane and isoflurane to activate a specific class of potassium channels. Because potassium channels are important regulators of neuronal excitability within the mammalian central nervous system, background channels such as the S channel may be responsible in part for mediating the action of volatile anesthetics.

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