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

TitleReduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1.
Publication TypeJournal Article
Year of Publication2007
AuthorsWestphalen RI, Krivitski M, Amarosa A, Guy N, Hemmings HC
JournalBr J Pharmacol
Date Published2007 Nov
KeywordsAnesthetics, Inhalation, Anesthetics, Local, Animals, Blotting, Western, Brain Chemistry, Cerebral Cortex, gamma-Aminobutyric Acid, Glutamic Acid, Halothane, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Endings, Neurotransmitter Agents, Potassium Channels, Tandem Pore Domain, Pulmonary Alveoli, Receptors, Presynaptic, Synaptosomes, Tetrodotoxin

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.

Alternate JournalBr. J. Pharmacol.
PubMed ID17828284
PubMed Central IDPMC2078222
Grant ListGM 58055 / GM / NIGMS NIH HHS / United States
R01 GM058055 / GM / NIGMS NIH HHS / United States