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

• Published in: British journal of pharmacology Vol. 152; no. 6; pp. 939 - 945
• Main Authors: Westphalen, R I, Krivitski, M, Amarosa, A, Guy, N, Hemmings, HC Jr
• Format: Journal Article
• Language: English
• Published: 01-11-2007
• ISSN: 0007-1188
• DOI: 10.1038/sj.bjp.0707450

Background and purpose: Deletion of TREK-1, a two-pore domain K super(+) channel (K sub(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 [ super(3)H]glutamate and [ super(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 super(+) channel and presynaptic function, and provides further support for presynaptic mechanisms in determining volatile anaesthetic action.