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The CNS under pathophysiologic attack—examining the role of K2P channels

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Abstract

Members of the two-pore domain K+ channel (K2P) family are increasingly recognized as being potential targets for therapeutic drugs and could play a role in the diagnosis and treatment of neurologic disorders. Their broad and diverse expression pattern in pleiotropic cell types, importance in cellular function, unique biophysical properties, and sensitivity toward pathophysiologic parameters represent the basis for their involvement in disorders of the central nervous system (CNS). This review will focus on multiple sclerosis (MS) and stroke, as there is growing evidence for the involvement of K2P channels in these two major CNS disorders. In MS, TASK1–3 channels are expressed on T lymphocytes and are part of a signaling network regulating Ca2+- dependent pathways that are mandatory for T cell activation, differentiation, and effector functions. In addition, TASK1 channels are involved in neurodegeneration, resulting in autoimmune attack of CNS cells. On the blood–brain barrier, TREK1 channels regulate immune cell trafficking under autoinflammatory conditions. Cerebral ischemia shares some pathophysiologic similarities with MS, including hypoxia and extracellular acidosis. On a cellular level, K2P channels can have both proapoptotic and antiapoptotic effects, either promoting neurodegeneration or protecting neurons from ischemic cell death. TASK1 and TREK1 channels have a neuroprotective effect on stroke development, whereas TASK2 channels have a detrimental effect on neuronal survival under ischemic conditions. Future research in preclinical models is needed to provide a more detailed understanding of the contribution of K2P channel family members to neurologic disorders, before translation to the clinic is an option.

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Abbreviations

ALA:

α-Linolenic acid

BBB:

Blood–brain barrier

BCR:

B cell receptor

CNS:

Central nervous system

CRAC:

Ca2+ release-activated channels

DAG:

Diacylglyceride

EAE:

Experimental autoimmune encephalomyelitis

GPCR:

G protein-coupled receptor

K2P :

Two-pore domain K+ channel

LPL:

Lysophospholipid

MCAO:

Medial cerebral artery occlusion

MOG:

Myelin oligodendrocyte glycoprotein

MS:

Multiple sclerosis

NOX4:

Nicotinamide adenine dinucleotide phosphate oxidase 4

PIP2 :

Phosphatidylinositol 4,5-bisphosphate

PLC:

Phospholipase C

PUFA:

Polyunsaturated fatty acid

TASK:

TWIK-related acid-sensitive K+ channel

Task1:

Task1 gene deficient

Th:

T helper cells

TCR:

T cell receptor

TRAAK:

TWIK-related arachidonic acid-stimulated K+ channel

TReg :

Regulatory T cells

TREK:

TWIK-related K+ channel

TRESK:

TWIK-related spinal cord K+ channel

TWIK:

The weak inwardly rectifying K+ channel

WT:

Wild-type

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Acknowledgments

We thank Heike Blum for excellent work on the graphical illustration. This work was supported by the Interdisciplinary Center for Clinical Research (IZKF) Münster (SEED 03/12 to SB; Meu3/010/12 to SGM), by Deutsche Forschungsgemeinschaft (FOR 1086, TP2 to TB and SGM; Cells-in-Motion Cluster of Excellence (EXC 1003–CiM) to PE, TB, SB and SGM), by Else Kröner-Fresenius-Stiftung (2012_A88 to SB and SGM), and by Innovative Medical Research (IMF) Münster (AL 121108 to PE).

Conflicts of interest

The authors report no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurology, University of Münster, Münster, Germany

    Petra Ehling, Sven G. Meuth & Stefan Bittner

  2. Department of Physiology I–Neuropathophysiology, University of Münster, Münster, Germany

    Manuela Cerina & Sven G. Meuth

  3. Department of Physiology I, University of Münster, Münster, Germany

    Thomas Budde

  4. Interdisciplinary Center for Clinical Research (IZKF), Münster, Germany

    Stefan Bittner

Authors
  1. Petra Ehling
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  2. Manuela Cerina
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  3. Thomas Budde
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  4. Sven G. Meuth
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  5. Stefan Bittner
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Corresponding author

Correspondence to Petra Ehling.

Additional information

Equal contributions by first authors Petra Ehling and Manuela Cerina and senior authors Sven G. Meuth and Stefan Bittner.

This article is intended to be published as part of the Special Issue on K2P channels.

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Ehling, P., Cerina, M., Budde, T. et al. The CNS under pathophysiologic attack—examining the role of K2P channels. Pflugers Arch - Eur J Physiol 467, 959–972 (2015). https://doi.org/10.1007/s00424-014-1664-2

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  • DOI: https://doi.org/10.1007/s00424-014-1664-2

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