| 17828284 |
Westphalen RI, Krivitski M, Amarosa A, Guy N, Hemmings HC Jr: 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. 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. |
93(1,1,2,8) |