TREK1 is a member of the tandem-P domain K+ channel family which is expressed almost exclusively in the nervous system. It is modulated by a number of important factors including arachidonic acid and cell swelling. Since both factors are associated with brain ischemia, it has been Suggested that activation of TREK1 may confer neuroprotection. However, it has been reported that the stably expressed human homologue of TREK I is inhibited by hypoxia, calling into question its neuroprotective role in ischemia. Here, using transient transfection of HEK 293 cells with several hTREK1 mutations and whole-cell patch-clamp. we show that: hypoxic inhibition: (a) requires the C-terminal domain of the channel: (b) does not involve redox modulation of the C-terminal domain cysteine residues C365 and C399; and (c) is critically dependent on the glutamate residue at position 306. These data suggest strongly that neuroprotection is unlikely to be provided by this channel in low O-2 environments and continue to cast a shadow of doubt over the precise role :hat TREK may have during hypoxic episodes. (c) 2005 Elsevier Inc. All rights reserved.