Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2012 Nov 23;28748:40425-32. doi: 10.1074/jbc.M112.405787.
Show Gene links
Show Anatomy links
Novel activation of voltage-gated K(+) channels by sevoflurane.
Barber AF
,
Liang Q
,
Covarrubias M
.
???displayArticle.abstract???
BACKGROUND: Halogenated inhaled anesthetics modulate voltage-gated ion channels by unknown mechanisms.
RESULTS: Biophysical analyses revealed novel activation of K(v) channels by the inhaled anesthetic sevoflurane.
CONCLUSION: K(v) channel activation by sevoflurane results from the positive allosteric modulation of activation gating.
SIGNIFICANCE: The unique activation of K(v) channels by sevoflurane demonstrates novel anesthetic specificity and offers new insights into allosteric modulation of channel gating. Voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, but the underlying molecular mechanisms are not understood. Alkanols and halogenated inhaled anesthetics such as halothane and isoflurane inhibit the archetypical voltage-gated Kv3 channel homolog K-Shaw2 by stabilizing the resting/closed states. By contrast, sevoflurane, a more heavily fluorinated ether commonly used in general anesthesia, specifically activates K-Shaw2 currents at relevant concentrations (0.05-1 mM) in a rapid and reversible manner. The concentration dependence of this modulation is consistent with the presence of high and low affinity interactions (K(D) = 0.06 and 4 mM, respectively). Sevoflurane (<1 mM) induces a negative shift in the conductance-voltage relation and increases the maximum conductance. Furthermore, suggesting possible roles in general anesthesia, mammalian Kv1.2 and Kv1.5 channels display similar changes. Quantitative description of the observations by an economical allosteric model indicates that sevoflurane binding favors activation gating and eliminates an unstable inactivated state outside the activation pathway. This study casts light on the mechanism of the novel sevoflurane-dependent activation of Kv channels, which helps explain how closely related inhaled anesthetics achieve specific actions and suggests strategies to develop novel Kv channel activators.
Barber,
Molecular mapping of general anesthetic sites in a voltage-gated ion channel.
2011, Pubmed
Barber,
Molecular mapping of general anesthetic sites in a voltage-gated ion channel.
2011,
Pubmed
Bhattacharji,
Inhalational anaesthetics and n-alcohols share a site of action in the neuronal Shaw2 Kv channel.
2010,
Pubmed
,
Xenbase
Bhattacharji,
The concerted contribution of the S4-S5 linker and the S6 segment to the modulation of a Kv channel by 1-alkanols.
2006,
Pubmed
,
Xenbase
Brannigan,
Multiple binding sites for the general anesthetic isoflurane identified in the nicotinic acetylcholine receptor transmembrane domain.
2010,
Pubmed
Cacheaux,
Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol.
2005,
Pubmed
,
Xenbase
Covarrubias,
Ethanol selectively blocks a noninactivating K+ current expressed in Xenopus oocytes.
1993,
Pubmed
,
Xenbase
Covarrubias,
Alcohols inhibit a cloned potassium channel at a discrete saturable site. Insights into the molecular basis of general anesthesia.
1995,
Pubmed
,
Xenbase
Downie,
Effects of inhalational general anaesthetics on native glycine receptors in rat medullary neurones and recombinant glycine receptors in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Eckenhoff,
Anesthetic mechanisms: worms light the way.
2011,
Pubmed
Eckenhoff,
Azi-isoflurane, a Photolabel Analog of the Commonly Used Inhaled General Anesthetic Isoflurane.
2010,
Pubmed
Forman,
Clinical and molecular pharmacology of etomidate.
2011,
Pubmed
Franks,
Molecular targets underlying general anaesthesia.
2006,
Pubmed
Franks,
General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal.
2008,
Pubmed
Franks,
Temperature dependence of the potency of volatile general anesthetics: implications for in vitro experiments.
1996,
Pubmed
Friederich,
Interaction of volatile anesthetics with human Kv channels in relation to clinical concentrations.
2001,
Pubmed
Hapfelmeier,
Sevoflurane potentiates and blocks GABA-induced currents through recombinant alpha1beta2gamma2 GABAA receptors: implications for an enhanced GABAergic transmission.
2001,
Pubmed
Harris,
General anesthetic action at an internal protein site involving the S4-S5 cytoplasmic loop of a neuronal K(+) channel.
2000,
Pubmed
,
Xenbase
Hemmings,
Emerging molecular mechanisms of general anesthetic action.
2005,
Pubmed
Herold,
Isoflurane inhibits the tetrodotoxin-resistant voltage-gated sodium channel Nav1.8.
2009,
Pubmed
Herrington,
Halothane inhibits two components of calcium current in clonal (GH3) pituitary cells.
1991,
Pubmed
Horishita,
The effects of volatile aromatic anesthetics on voltage-gated Na+ channels expressed in Xenopus oocytes.
2008,
Pubmed
,
Xenbase
Jenkins,
Actions of general anaesthetics on 5-HT3 receptors in N1E-115 neuroblastoma cells.
1996,
Pubmed
Krasowski,
General anaesthetic actions on ligand-gated ion channels.
1999,
Pubmed
Ledwell,
Mutations in the S4 region isolate the final voltage-dependent cooperative step in potassium channel activation.
1999,
Pubmed
,
Xenbase
Nury,
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel.
2011,
Pubmed
Ouyang,
Comparative effects of halogenated inhaled anesthetics on voltage-gated Na+ channel function.
2009,
Pubmed
OuYang,
Isoform-selective effects of isoflurane on voltage-gated Na+ channels.
2007,
Pubmed
Patel,
Inhalational anesthetics activate two-pore-domain background K+ channels.
1999,
Pubmed
Putzke,
Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1.
2007,
Pubmed
,
Xenbase
Scheller,
Isoflurane and sevoflurane interact with the nicotinic acetylcholine receptor channels in micromolar concentrations.
1997,
Pubmed
Shiraishi,
Effects of alcohols and anesthetics on recombinant voltage-gated Na+ channels.
2004,
Pubmed
,
Xenbase
Singaram,
Optical reversal of halothane-induced immobility in C. elegans.
2011,
Pubmed
Smith-Maxwell,
Role of the S4 in cooperativity of voltage-dependent potassium channel activation.
1998,
Pubmed
,
Xenbase
Stevens,
Molecular properties important for inhaled anesthetic action on human 5-HT3A receptors.
2005,
Pubmed
,
Xenbase
Stevens,
Modulation of human 5-hydroxytryptamine type 3AB receptors by volatile anesthetics and n-alcohols.
2005,
Pubmed
,
Xenbase
Suzuki,
The diverse actions of volatile and gaseous anesthetics on human-cloned 5-hydroxytryptamine3 receptors expressed in Xenopus oocytes.
2002,
Pubmed
,
Xenbase
Takenoshita,
Halothane blocks low-voltage-activated calcium current in rat sensory neurons.
1991,
Pubmed
Todorovic,
Anticonvulsants but not general anesthetics have differential blocking effects on different T-type current variants.
2000,
Pubmed
Tsunoda,
Genetic analysis of Drosophila neurons: Shal, Shaw, and Shab encode most embryonic potassium currents.
1995,
Pubmed
Urban,
The site of anesthetic action.
2008,
Pubmed
Vedula,
A unitary anesthetic binding site at high resolution.
2009,
Pubmed
Willenbring,
Isoflurane alters the structure and dynamics of GLIC.
2011,
Pubmed
Zagotta,
Shaker potassium channel gating. III: Evaluation of kinetic models for activation.
1994,
Pubmed
,
Xenbase
