Polymodal regulation of hTREK1 by pH, arachidonic acid, and hypoxia: physiological impact in acidosis and alkalosis

Abstract

Miller, Paula, Chris Peers, and Paul J. Kemp. Polymodal regulation of hTREK1 by pH, arachidonic acid, and hypoxia: physiological impact in acidosis and alkalosis. Am J Physiol Cell Physiol 286: C272-C282, 2004. First published October 1, 2003 10.1152/ ajpcell.00334.2003.-Expression of the human tandem P domain K ϩ channel, hTREK1, is limited almost exclusively to the central nervous system, where ambient PO 2 can be as low as 20 Torr. We have previously shown that this level of hypoxia evokes a maximal inhibitory influence on recombinant hTREK1 and occludes the activation by arachidonic acid; this has cast doubt on the idea that TREK1 activation during brain ischemia could facilitate neuroprotection via hyperpolarizing neurons in which it is expressed. Using both whole cell and cell-attached patch-clamp configurations, we now show that the action of another potent TREK activator and ischemia-related event, intracellular acidification, is similarly without effect during compromised O2 availability. This occlusion is observed in either recording condition, and even the concerted actions of both arachidonic acid and intracellular acidosis are unable to activate hTREK1 during hypoxia. Conversely, intracellular alkalinization is a potent channel inhibitor, and hypoxia does not reverse this inhibition. However, increases in intracellular pH are unable to occlude either arachidonic acid activation or hypoxic inhibition. These data highlight two important points. First, during hypoxia, modulation of hTREK1 cannot be accomplished by parameters known to be perturbed in brain ischemia (increased extracellular fatty acids and intracellular acidification). Second, the mechanism of regulation by intracellular alkalinization is distinct from the overlapping structural requirements known to exist for regulation by arachidonic acid, membrane distortion, and acidosis. Thus it seems likely that hTREK1 regulation in the brain will be physiologically more relevant during alkalosis than during ischemia or acidosis. potassium channel; tandem P domain THE TANDEM P DOMAIN potassium channel TREK1 is localized almost exclusively to the central nervous system (CNS), where it is believed to play a key role in setting the resting membrane potential of the neurons in which it is expressed (4,12,16,17). Evidence also exists for its expression in the peripheral nervous system, in general and sensory neurons of the dorsal root ganglion in particular (12). On the basis of the ability of TREK to influence the resting membrane potential of neurons, coupled to evidence of its specific regulation by unsaturated fatty acids (4, 15, 23), membrane stretch (23), acidosis (12, 13), and inhalation anesthetics (22), it has been suggested that this background K ϩ channel may control neuronal excitability and play a neuroprotective role during brain ischemia, where local pH declines and arachidonic acid is released into the extracellular space (see, for example, Ref. 24). Further support for such an idea has come from the demonstration that the neuroprotecti...

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

“…IIIC6). Although the relevance of the above conclusions has been questioned by reports which suggested that TREK current is not stimulated under hypoxic conditions (235,236), the effect of PUFA on TREK was repeatedly corroborated by other studies (35,44).…”

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

“…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 Tandem P Domain K+Channel, TREK-1, in the Rat Carotid Body

“…Miller et al (2003) reported that acute hypoxia occluded human TREK-1 expressed in the HEK293 cells under ischemic and/or acidotic conditions. Furthermore, it is reported that inhibited TREK-1 current by intracellular alkanization was further suppressed by hypoxia (Miller et al 2004). On the contrary, other reports demonstrated that TREK-1 was not oxygen sensitive (Buckler and Honore 2005;Caley et al 2005).…”