Abstract
Cerebral stroke is a worldwide leading cause of disability. The two-pore domain K+ channels identified as background channels are involved in many functions in brain under physiological and pathological conditions. We addressed the hypothesis that TRAAK, a mechano-gated and lipid-sensitive two-pore domain K+ channel, is involved in the pathophysiology of brain ischemia. We studied the effects of TRAAK deletion on brain morphology and metabolism under physiological conditions, and during temporary focal cerebral ischemia in Traak−/− mice using a combination of in vivo magnetic resonance imaging (MRI) techniques and multinuclear magnetic resonance spectroscopy (MRS) methods. We provide the first in vivo evidence establishing a link between TRAAK and neurometabolism. Under physiological conditions, Traak−/− mice showed a particular metabolic phenotype characterized by higher levels of taurine and myo-inositol than Traak+/+ mice. Upon ischemia, Traak−/− mice had a smaller infarcted volume, with lower contribution of cellular edema than Traak+/+ mice. Moreover, brain microcirculation was less damaged, and brain metabolism and pH were preserved. Our results show that expression of TRAAK strongly influences tissue levels of organic osmolytes. Traak−/− mice resilience to cellular edema under ischemia appears related to their physiologically high levels of myo-inositol and of taurine, an aminoacid involved in the modulation of mitochondrial activity and cell death. The beneficial effects of TRAAK deletion designate this channel as a promising pharmacological target for the treatment against stroke.
Highlights
Potassium (K+) channels are involved in many cellular functions and considered as promising pharmacological targets for the treatment of neurodegenerative diseases and cerebral stroke, a worldwide leading cause of disability [1]
We addressed the hypothesis that TRAAK is involved in the pathophysiology of brain ischemia by studying a model of transient occlusion of the middle cerebral artery [6,12]
We report that TRAAK deletion is protective against cerebral transient focal ischemia
Summary
Potassium (K+) channels are involved in many cellular functions and considered as promising pharmacological targets for the treatment of neurodegenerative diseases and cerebral stroke, a worldwide leading cause of disability [1]. In the central nervous system, they participate to neuronal K+ release and spatial glial K+ buffering [3] They are designated as the background K+ channels maintaining resting membrane potential and are quasiinsensitive to classic K+ blockers [2,4,5]. Among K2P channels, TREK channels, which are regulated by neurotransmitters and hormones [2,5], form the first identified lipid- and stretch-activated K2P channels, with three members TREK-1 (K2P2.1 or KCNK2), TREK-2 (K2P10.1 or KCNK10) and TRAAK (K2P4.1 or KCNK4) [6] Because these channels are activated by potent neuroprotectors such as polyunsaturated fatty acids (PUFA), it has been suggested that they could all be involved in neuroprotection [6]. The implication of TREK-1 has been identified in several neurological conditions including ischemia [6,12]
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