Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane.

@article{Gruss2004TwoporedomainKC,
  title={Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane.},
  author={Marco Gruss and Trevor J Bushell and Damian P. Bright and William Robert Lieb and Alistair Mathie and Nicholas P. Franks},
  journal={Molecular pharmacology},
  year={2004},
  volume={65 2},
  pages={
          443-52
        }
}
Nitrous oxide, xenon, and cyclopropane are anesthetic gases that have a distinct pharmacological profile. Whereas the molecular basis for their anesthetic actions remains unclear, they behave very differently to most other general anesthetics in that they have little or no effect on GABAA receptors, yet strongly inhibit the N-methyl-d-aspartate subtype of glutamate receptors. Here we show that certain members of the two-pore-domain K+ channel superfamily may represent an important new target… 

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References

SHOWING 1-10 OF 47 REFERENCES

The TASK-1 Two-Pore Domain K+ Channel Is a Molecular Substrate for Neuronal Effects of Inhalation Anesthetics

Evidence is presented implicating the two-pore domain, pH-sensitive TASK-1 channel as a target for specific, clinically important anesthetic effects in mammalian neurons, in rat somatic motoneurons and locus coeruleus cells.

Effects of Gaseous Anesthetics Nitrous Oxide and Xenon on Ligand-gated Ion Channels: Comparison with Isoflurane and Ethanol

The results suggest that NMDA receptors and nACh receptors composed of &bgr;2 subunits are likely targets for nitrous oxide and xenon, which are distinct from that of isoflurane or ethanol.

Anesthetic-sensitive 2P Domain K+ Channels

The expression and properties of these anesthetic-sensitive K channels are reviewed, and their possible functional role in the mechanisms of anesthesia and analgesia is discussed.

Inhalational anesthetics activate two-pore-domain background K+ channels

It is shown that TASK and TREK-1, two recently cloned mammalian two-P-domain K+ channels similar to IKAn in biophysical properties, are activated by volatile general anesthetics.

Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) Potassium Channels

Both anesthetic activation and transmitter inhibition of these channels require a region at the interface between the final transmembrane domain and the cytoplasmic C terminus that has not been associated previously with receptor signal transduction.

Volatile general anaesthetics activate a novel neuronal K+ current

It is reported that amongst a group of apparently identical molluscan neurons having endogenous firing activity, a single cell displays an unusual sensitivity to volatile agents (which, at surgical levels, completely inhibit its activity); it is shown that this sensitivity is due to a novel anaesthetic-activated K+ current, which is found in the sensitive cell but not in the surrounding insensitive cells.

TOK1 Is a Volatile Anesthetic Stimulated K+ Channel

To investigate whether cloned ion channels with electrophysiologic properties similar to the S channel also are modulated by volatile anesthetic agents, cloned yeast ion channel TOK1 was expressed in Xenopus oocytes and studied its sensitivity to volatile agents.

Anesthetics and ion channels: molecular models and sites of action.

This review summarizes from a molecular perspective recent advances in the understanding of mechanisms of action of general anesthetics on ligand-gated ion channels.

Mechano- or Acid Stimulation, Two Interactive Modes of Activation of the TREK-1 Potassium Channel*

It is shown that internal acidification opens TREK-1, a member of the novel structural class of K+ channels with four transmembrane segments and two pore domains in tandem, and lowering pH i shifts the pressure-activation relationship toward positive values and leads to channel opening at atmospheric pressure.

A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons.

This description of a functional two-pore domain potassium channel in the mammalian central nervous system indicates its physiological importance in controlling cell excitability and how agents that modify its activity, such as agonists at G protein-coupled receptors and hydrogen ions, can profoundly alter both the neuron's resting potential and its excitability.