Acute hypoxia occludes hTREK-1 modulation: re-evaluation of the potential role of tandem P domain K+ channels in central neuroprotection

Abstract

The human tandem P domain K+ channel hTREK-1 (KCNK2) is distributed widely through the CNS. Here, whole-cell patch clamp recordings were employed to investigate the effects of hypoxia on hTREK-1 channels stably expressed in human embryonic kidney cells. Acute hypoxia caused a rapid and reversible inhibition of whole-cell K+ current amplitudes; this was PO2 dependent with a maximal inhibition achieved at 60 mmHg and below. In accordance with previous studies, hTREK-1 current amplitudes were enhanced by arachidonic acid. This effect was concentration dependent, with maximal enhancement observed at a concentration of 10 microM. Membrane deformation by the crenator trinitrophenol (to mimic cell swelling) or the cup former chlorpromazine (to mimic cell shrinkage) caused robust activation and inhibition of currents, respectively. However, current augmentation by either arachidonic acid or trinitrophenol was completely prevented during hypoxia; conversely, hypoxia blunted the inhibitory action of chlorpromazine. The abilities of arachidonic acid to augment currents and of hypoxia to completely abrogate this effect were also observed in cell-attached patches. Our data indicate that hypoxia interacts with hTREK-1, and occludes its modulation by arachidonic acid and membrane deformation. These findings also suggest that the potential neuroprotective role of TREK channels, which has recently been proposed, requires reconsideration since hTREK-1 activation is unlikely when ambient PO2 is below 60 mmHg - a situation which normally pertains in the CNS even during systemic normoxia.

Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1

“…Therefore, it is difficult to explain the role of TREK-1 in neuroprotection. One possibility is that this property may depend on the expression pattern of TREK-1 [31,38,40,41] . Further investigation into the role of TREK-1 in neuronal damage/protection is needed.…”

“…Therefore, l-NBP-mediated inhibition of TREK-1 channels may help to maintain or increase the function of glutamate uptake by astrocytes during brain ischemia. Furthermore, the TREK-1 channel is known to be an O 2 -sensitive K + channel, and acute hypoxia can occlude its activation by AA and other activators [38,39] . This finding suggests that TREK-1 may not be activated during systemic hypoxia (as occurs during cerebral ischemia).…”

Expression of TASK and TREK, two-pore domain K+ channels, in human myometrium

“…Functionally, TASK channels are exquisitely sensitive to perturbations in extracellular pH: acidosis inhibits TASK currents whereas alkalosis increases the current (Duprat et al 1997). TREK channels, on the other hand, are modulated by membrane stretch and arachidonic acid (Bang et al 2000, Miller et al 2003. One common regulatory mechanism, described for TASK1, TASK3 and TREK1 is their inhibition by hypoxia , Miller et al 2003.…”

“…However, it is becoming more evident that these channels have diverse mechanisms of modulation. Factors influencing these channels include extracellular pH (Duprat et al 1997), membrane stretch, arachidonic acid (Bang et al 2000, Miller et al 2003 and oxygen tension (hypoxia; Lewis et al 2001, Miller et al 2003.…”

The Inhibition of TREK2 Channel by an Oxidizing Agent, 5,5'-dithio-bis (2-nitrobenzoic acid), via Interaction with the C-terminus Distal to the 353rd Amino Acid

“…Among these sub-families, TASK1, TASK3 and TREK1 have previously been reported as candidates for oxygen-sensing channels, although the effect of hypoxia on TREK1 still remains controversial (Buckler and Honore, 2005;Caley et al, 2005;Miller et al, 2003;Miller et al, 2005;Miller et al, 2004). Inhibition of TREK1 by hypoxia requires the C-terminus of the channel (Miller et al, 2005), and structural modification of the channel can also lead to hypoxic effects.…”