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      TASK-1 channels in oligodendrocytes: A role in ischemia mediated disruption

      research-article
      Author(s): , *
      Publication date PMC-release:
      Journal: Neurobiology of Disease
      Publisher: Academic Press
      Keywords: Brain, White matter, Potassium channels, Glia, Oligodendrocyte

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          Abstract

          Oligodendrocytes are the myelinating cells of the CNS and, like neurons, are highly sensitive to ischemic damage. However, the mechanisms underlying cytotoxicity in oligodendrocytes during hypoxic/ischemic episodes are not fully understood. TASK-1 is a K + leak channel that mediates hypoxic depolarisation in neurons. The expression and function of TASK-1 in oligodendrocytes had not previously been addressed. In this study, we investigate the expression of TASK-1 in oligodendrocytes and its role in white matter ischemic damage. Expression of TASK-1 in oligodendrocytes was investigated in the mouse brain using immunostaining. TASK-1 channel function was identified by established pharmacological and electrophysiological strategies, using the whole-cell patch clamp technique in cell cultures of oligodendrocytes from the optic nerve, a typical white matter tract. The role of TASK-1 in hypoxia was examined in isolated intact optic nerves subjected to oxygen glucose deprivation (OGD). Oligodendrocytes are strongly immunopositive for TASK-1 throughout the brain. Patch-clamp identified functional TASK-1-like leak currents in oligodendrocytes using two recognised means of inhibiting TASK-1, decreasing extracellular pH to 6.4 and exposure to the TASK-1 selective inhibitor anandamide. Incubation of optic nerves with methanandamide, a non-hydrolysable form of anandamide, significantly protected oligodendrocytes against hypoxic disruption and death in OGD. Our data demonstrate for the first time that oligodendrocytes express functional TASK-1 channels and provide compelling evidence they contribute to oligodendrocyte damage in hypoxia. Since oligodendrocyte damage is a key factor in ischemic episodes, TASK-1 may provide a potential therapeutic target in stroke and white matter disease.

          Highlights

          • •

            TASK-1 subtype of K 2P channel is involved in ischemic neuronal damage.

          • •

            Oligodendrocytes, the myelinating cells of the CNS, are highly sensitive to ischemic damage.

          • •

            We demonstrate functional expression of TASK-1 in oligodendrocytes.

          • •

            Inhibition of TASK1 with anandamide significantly protected against oligodendrocyte damage in response to ischemia.

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          Most cited references42

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          NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury.

          Robert Fern, Donald Salter (2005)
          Injury to oligodendrocyte processes, the structures responsible for myelination, is implicated in many forms of brain disorder. Here we show NMDA (N-methyl-D-aspartate) receptor subunit expression on oligodendrocyte processes, and the presence of NMDA receptor subunit messenger RNA in isolated white matter. NR1, NR2A, NR2B, NR2C, NR2D and NR3A subunits showed clustered expression in cell processes, but NR3B was absent. During modelled ischaemia, NMDA receptor activation resulted in rapid Ca2+-dependent detachment and disintegration of oligodendroglial processes in the white matter of mice expressing green fluorescent protein (GFP) specifically in oligodendrocytes (CNP-GFP mice). This effect occurred at mouse ages corresponding to both the initiation and the conclusion of myelination. NR1 subunits were found mainly in oligodendrocyte processes, whereas AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor subunits were mainly found in the somata. Consistent with this observation, injury to the somata was prevented by blocking AMPA/kainate receptors, and preventing injury to oligodendroglial processes required the blocking of NMDA receptors. The presence of NMDA receptors in oligodendrocyte processes explains why previous studies that have focused on the somata have not detected a role for NMDA receptors in oligodendrocyte injury. These NMDA receptors bestow a high sensitivity to acute injury and represent an important new target for drug development in a variety of brain disorders.
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            Regulation of oligodendrocyte development and myelination by glucose and lactate.

            Johanne E. Rinholm, Nicola B. Hamilton, Nicoletta Kessaris … (2011)
            In the gray matter of the brain, astrocytes have been suggested to export lactate (derived from glucose or glycogen) to neurons to power their mitochondria. In the white matter, lactate can support axon function in conditions of energy deprivation, but it is not known whether lactate acts by preserving energy levels in axons or in oligodendrocytes, the myelinating processes of which are damaged rapidly in low energy conditions. Studies of cultured cells suggest that oligodendrocytes are the cell type in the brain that consumes lactate at the highest rate, in part to produce membrane lipids presumably for myelin. Here, we use pH imaging to show that oligodendrocytes in the white matter of the rat cerebellum and corpus callosum take up lactate via monocarboxylate transporters (MCTs), which we identify as MCT1 by confocal immunofluorescence and electron microscopy. Using cultured slices of developing cerebral cortex from mice in which oligodendrocyte lineage cells express GFP (green fluorescent protein) under the control of the Sox10 promoter, we show that a low glucose concentration reduces the number of oligodendrocyte lineage cells and myelination. Myelination is rescued when exogenous l-lactate is supplied. Thus, lactate can support oligodendrocyte development and myelination. In CNS diseases involving energy deprivation at times of myelination or remyelination, such as periventricular leukomalacia leading to cerebral palsy, stroke, and secondary ischemia after spinal cord injury, lactate transporters in oligodendrocytes may play an important role in minimizing the inhibition of myelination that occurs.
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              Molecular and functional properties of two-pore-domain potassium channels.

              M Lazdunski, F. Lesage (2000)
              The two-pore-domain K(+) channels, or K(2P) channels, constitute a novel class of K(+) channel subunits. They have four transmembrane segments and are active as dimers. The tissue distribution of these channels is widespread, and they are found in both excitable and nonexcitable cells. K(2P) channels produce currents with unusual characteristics. They are quasi-instantaneous and noninactivating, and they are active at all membrane potentials and insensitive to the classic K(+) channel blockers. These properties designate them as background K(+) channels. They are expected to play a major role in setting the resting membrane potential in many cell types. Another salient feature of K(2P) channels is the diversity of their regulatory mechanisms. The weak inward rectifiers TWIK-1 and TWIK-2 are stimulated by activators of protein kinase C and decreased by internal acidification, the baseline TWIK-related acid-sensitive K(+) (TASK)-1 and TASK-2 channels are sensitive to external pH changes in a narrow range near physiological pH, and the TWIK-related (TREK)-1 and TWIK-related arachidonic acid-stimulated K(+) (TRAAK) channels are the first cloned polyunsaturated fatty acids-activated and mechanogated K(+) channels. The recent demonstration that TASK-1 and TREK-1 channels are activated by inhalational general anesthetics, and that TRAAK is activated by the neuroprotective agent riluzole, indicates that this novel class of K(+) channels is an interesting target for new therapeutic developments.
              Article 0 comments Cited 77 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Neurobiol Dis
                Journal ID (iso-abbrev): Neurobiol. Dis
                Title: Neurobiology of Disease
                Publisher: Academic Press
                ISSN (Print): 0969-9961
                ISSN (Electronic): 1095-953X
                Publication date PMC-release: 1 July 2013
                Publication date (Print): July 2013
                Volume: 55
                Issue: 100
                Pages: 87-94
                Affiliations
                Institute of Biomedical and Biomolecular Science, University of Portsmouth, St Michael's Building, White Swan Rd, Portsmouth, PO1 2DT, UK
                Author notes
                [* ]Corresponding author. Fax: + 44 2392842156. arthur.butt@ 123456port.ac.uk
                Article
                Publisher ID: YNBDI2941
                DOI: 10.1016/j.nbd.2013.03.016
                PMC ID: 3657199
                PubMed ID: 23567653
                SO-VID: 9c0a1493-d4da-4e91-a258-23a3da0287e9
                Copyright © © 2013 Elsevier Inc.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 16 January 2013
                Date revision received : 13 March 2013
                Date accepted : 29 March 2013
                Categories
                Subject: Article

                ScienceOpen disciplines: Neurosciences
                Keywords: brain,white matter,potassium channels,glia,oligodendrocyte
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: brain, white matter, potassium channels, glia, oligodendrocyte

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