Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1

Br J Pharmacol. 2007 Nov;152(6):939-45. doi: 10.1038/sj.bjp.0707450. Epub 2007 Sep 10.


Background and purpose: Deletion of TREK-1, a two-pore domain K(+) channel (K(2P)) activated by volatile anaesthetics, reduces volatile anaesthetic potency in mice, consistent with a role for TREK-1 as an anaesthetic target. We used TREK-1 knockout mice to examine the presynaptic function of TREK-1 in transmitter release and its role in the selective inhibition of glutamate vs GABA release by volatile anaesthetics.

Experimental approach: The effects of halothane on 4-aminopyridine-evoked and basal [(3)H]glutamate and [(14)C]GABA release from cerebrocortical nerve terminals isolated from TREK-1 knockout (KO) and littermate wild-type (WT) mice were compared. TREK-1 was quantified by immunoblotting of nerve terminal preparations.

Key results: Deletion of TREK-1 significantly reduced the potency of halothane inhibition of 4-aminopyridine-evoked release of both glutamate and GABA without affecting control evoked release or the selective inhibition of glutamate vs GABA release. TREK-1 deletion also reduced halothane inhibition of basal glutamate release, but did not affect basal GABA release.

Conclusions and implications: The reduced sensitivity of glutamate and GABA release to inhibition by halothane in TREK-1 KO nerve terminals correlates with the reduced anaesthetic potency of halothane in TREK-1 KO mice observed in vivo. A presynaptic role for TREK-1 was supported by the enrichment of TREK-1 in isolated nerve terminals determined by immunoblotting. This study represents the first evidence for a link between an anaesthetic-sensitive 2-pore domain K(+) channel and presynaptic function, and provides further support for presynaptic mechanisms in determining volatile anaesthetic action.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anesthetics, Inhalation / pharmacology*
  • Anesthetics, Local / pharmacology
  • Animals
  • Blotting, Western
  • Brain Chemistry / drug effects
  • Brain Chemistry / genetics
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Glutamic Acid / metabolism*
  • Halothane / pharmacology*
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Endings / drug effects
  • Nerve Endings / metabolism
  • Neurotransmitter Agents / metabolism
  • Potassium Channels, Tandem Pore Domain / genetics*
  • Potassium Channels, Tandem Pore Domain / metabolism
  • Potassium Channels, Tandem Pore Domain / physiology*
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism
  • Receptors, Presynaptic / drug effects
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Tetrodotoxin / pharmacology
  • gamma-Aminobutyric Acid / metabolism*


  • Anesthetics, Inhalation
  • Anesthetics, Local
  • Neurotransmitter Agents
  • Potassium Channels, Tandem Pore Domain
  • Receptors, Presynaptic
  • potassium channel protein TREK-1
  • Glutamic Acid
  • Tetrodotoxin
  • gamma-Aminobutyric Acid
  • Halothane