The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice

Meuth, Sven G.; Kleinschnitz, Christoph; Broicher, Tilman; Austinat, Madeleine; Braeuninger, Stefan; Bittner, Stefan; Fischer, Stefan; Bayliss, Douglas A.; Budde, Thomas; Stoll, Guido; Wiendl, Heinz

doi:10.1016/j.nbd.2008.09.006

Cited by 50 publications

(41 citation statements)

References 54 publications

(82 reference statements)

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“…The regulation of specific g L s (TASK1) has been implicated in maintaining resting potential, input resistance, and the adaptive response to hypoxia or stroke development. They can be modulated by neurotransmitters and can shut down axon conduction when overactivated by anesthetics (29). The modulation of potassium-mediated leak currents by neurotransmitter has also been observed in autonomic neurons and in central myelinated and unmyelinated nerves (30)(31)(32).…”

Section: Discussionmentioning

confidence: 97%

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Coggan

Prescott

Bartol

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Fast axonal conduction of action potentials in mammals relies on myelin insulation. Demyelination can cause slowed, blocked, desynchronized, or paradoxically excessive spiking that underlies the symptoms observed in demyelination diseases. The diversity and timing of such symptoms are poorly understood, often intermittent, and uncorrelated with disease progress. We modeled the effects of demyelination (and secondary remodeling) on intrinsic axonal excitability using Hodgkin-Huxley and reduced Morris-Lecar models. Simulations and analysis suggested a simple explanation for the breadth of symptoms and revealed that the ratio of sodium to leak conductance, g Na /g L , acted as a four-way switch controlling excitability patterns that included spike failure, single spike transmission, afterdischarge, and spontaneous spiking. Failure occurred when this ratio fell below a threshold value. Afterdischarge occurred at g Na /g L just below the threshold for spontaneous spiking and required a slow inward current that allowed for two stable attractor states, one corresponding to quiescence and the other to repetitive spiking. A neuron prone to afterdischarge could function normally unless it was switched to its "pathological" attractor state; thus, although the underlying pathology may develop slowly by continuous changes in membrane conductances, a discontinuous change in axonal excitability can occur and lead to paroxysmal symptoms. We conclude that tonic and paroxysmal positive symptoms as well as negative symptoms may be a consequence of varying degrees of imbalance between g Na and g L after demyelination. The KCNK family of g L potassium channels may be an important target for new drugs to treat the symptoms of demyelination. O ligodendrocytes and Schwann cells tightly wrap axons at regular intervals to form the myelin sheath that allows for rapid axonal conduction. Neuropathies involving axonal demyelination are characterized by the unraveling of this insulation and can affect both the central nervous system, as in the case of multiple sclerosis (MS), and the peripheral nervous system, as in Guillain-Barré syndrome.Causes of demyelination include immunologic disease processes, as well as lesions such as traumatic nerve damage, nonpenetrating spinal cord injuries, and chronic nerve compression (1-4). Regardless of the precise etiology, clinical presentation often involves negative (loss-of-function) symptoms, including loss of motor control (i.e., paresis) and sensory deficits such as blindness and numbness, as well as positive (gain-of-function) symptoms, including muscle spasms, tactile allodynia, and chronic pain that is constant or paroxysmal (1, 4-7). Which muscles or sensory modalities are affected depends on where in the nervous system the demyelinating lesions develop, but changes in conduction velocity alone are clearly insufficient to explain the breadth of symptoms observed, especially the positive ones. In particular, MS often produces confounding symptoms that can present intermittently, resolving and retu...

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Section: Discussionmentioning

confidence: 97%

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Coggan

Prescott

Bartol

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Genetic deletion or pharmacological blockade of KCNK3 (TASK1) increased infarct volumes in different stroke models with transient artery occlusion [49] or permanent artery occlusion [52]. It is assumed that KCNK3 mediates a protective hyperpolarizing effect on neurons after cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%

“…Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) in 6-to 8-week-old male C57BL/6 wild-type (WT) mice (Charles River) and Kcnk5 −/− mice [6], weighing between 20 and 25 g, using the intraluminal filament technique [49]. Mice were anesthetized with 2.0 % isoflurane, and core body temperature was maintained at 37°C throughout surgery.…”

Section: Stroke Modelmentioning

confidence: 99%

The two-pore domain potassium channel KCNK5 deteriorates outcome in ischemic neurodegeneration

Göb

Bittner

Bobak

et al. 2014

Pflugers Arch - Eur J Physiol

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Potassium channels can fulfill both beneficial and detrimental roles in neuronal damage during ischemic stroke. Earlier studies have characterized a neuroprotective role of the two-pore domain potassium channels KCNK2 (TREK1) and KCNK3 (TASK1). Protective neuronal hyperpolarization and prevention of intracellular Ca(2+) overload and glutamate excitotoxicity were suggested to be the underlying mechanisms. We here identify an unexpected role for the related KCNK5 channel in a mouse model of transient middle cerebral artery occlusion (tMCAO). KCNK5 is strongly upregulated on neurons upon cerebral ischemia, where it is most likely involved in the induction of neuronal apoptosis. Hypoxic conditions elevated neuronal expression levels of KCNK5 in acute brain slices and primary isolated neuronal cell cultures. In agreement, KCNK5 knockout mice had significantly reduced infarct volumes and improved neurologic function 24 h after 60 min of tMCAO and this protective effect was preserved at later stages of infarct development. KCNK5 deficiency resulted in a significantly reduced number of apoptotic neurons, a downregulation of pro-apoptotic and upregulation of anti-apoptotic factors. Results of adoptive transfer experiments of wild-type and Kcnk5 (-/-) immune cells into Rag1 (-/-) mice prior to tMCAO exclude a major role of KCNK5 in poststroke inflammatory reactions. In summary, KCNK5 expression is induced on neurons under ischemic conditions where it most likely exerts pro-apoptotic effects. Hence, pharmacological blockade of KCNK5 might have therapeutic potential in preventing ischemic neurodegeneration.

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“…Hypoxia and extracellular acidosis, occurring under conditions such as trauma, cerebral ischemia, stroke and inflammation, inhibit TASK-1 channel function leading to membrane depolarization, which can contribute to susceptibility to brain damage. Studies have shown that pharmacological block of TASK channels increases infarct volumes and accelerates stroke development in mice undergoing transient middle cerebral artery occlusion (Bittner et al 2010;Meuth et al 2009). In addition, compared to wild-type, TASK-1 KO mice reported to have larger infarct volumes accompanied by worse outcomes in functional tests following middle cerebral artery occlusion (Bittner et al 2010;Meuth et al 2009;Muhammad et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Studies have shown that pharmacological block of TASK channels increases infarct volumes and accelerates stroke development in mice undergoing transient middle cerebral artery occlusion (Bittner et al 2010;Meuth et al 2009). In addition, compared to wild-type, TASK-1 KO mice reported to have larger infarct volumes accompanied by worse outcomes in functional tests following middle cerebral artery occlusion (Bittner et al 2010;Meuth et al 2009;Muhammad et al 2010). Increased susceptibility of TASK-1 KO animals to brain injury is not completely understood; it may be due to decreased neuroprotection (Bittner et al 2010;Meuth et al 2009), or may be a result of reduced blood pressure involving non-neuronal mechanisms (Muhammad et al 2010).…”

Section: Introductionmentioning

confidence: 99%

The two-pore domain K+ channel TASK-1 is closely associated with brain barriers and meninges

et al. 2010

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Impairment of the blood-brain barrier (BBB), the blood-cerebrospinal fluid (CSF) barrier and brain-CSF barrier has been implicated in neuropathology of several brain disorders, such as amyotrophic lateral sclerosis, cerebral edema, multiple sclerosis, neural inflammation, ischemia and stroke. Two-pore domain weakly inward rectifying K+ channel (TWIK)-related acid-sensitive potassium (TASK)-1 channels (K2p3.1; KCNK3) are among the targets that contribute to the development of these pathologies. For example TASK-1 activity is inhibited by acidification, ischemia, hypoxia and several signaling molecules released under pathologic conditions. We have used immuno-histochemistry to examine the distribution of the TASK-1 protein in structures associated with the BBB, blood-CSF barrier, brain-CSF barrier, and in the meninges of adult rat. Dense TASK-1 immuno-reactivity (TASK-1-IR) was observed in ependymal cells lining the fourth ventricle at the brain-CSF interface, in glial cells that ensheath the walls of blood vessels at the glio-vascular interface, and in the meninges. In these structures, TASK-1-IR often co-localized with glial fibrillary associated protein (GFAP) or vimentin. This study provides anatomical evidence for localization of TASK-1 K+ channels in cells that segregate distinct fluid compartments within and surrounding the brain. We suggest that TASK-1 channels, in coordination with other ion channels (e.g., aquaporins and chloride channels) and transporters (e.g., Na+-K+-ATPase and Na+-K+-2Cl⁻ and by virtue of its heterogeneous distribution, may differentially contribute to the varying levels of K+ vital for cellular function in these compartments. Our findings are likely to be relevant to recently reported roles of TASK-1 in cerebral ischemia, stroke and inflammatory brain disorders.

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The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice

Cited by 50 publications

References 54 publications

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

The two-pore domain potassium channel KCNK5 deteriorates outcome in ischemic neurodegeneration

The two-pore domain K+ channel TASK-1 is closely associated with brain barriers and meninges

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