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Ion fluxes mediated by glial cells are required for several physiological processes such as fluid homeostasis or the maintenance of low extracellular potassium during high neuronal activity. In mice, the disruption of the Cl(-) channel ClC-2 causes fluid accumulation leading to myelin vacuolation. A similar vacuolation phenotype is detected in humans affected with megalencephalic leukoencephalopathy with subcortical cysts (MLC), a leukodystrophy which is caused by mutations in MLC1 or GLIALCAM. We here identify GlialCAM as a ClC-2 binding partner. GlialCAM and ClC-2 colocalize in Bergmann glia, in astrocyte-astrocyte junctions at astrocytic endfeet around blood vessels, and in myelinated fiber tracts. GlialCAM targets ClC-2 to cell junctions, increases ClC-2 mediated currents, and changes its functional properties. Disease-causing GLIALCAM mutations abolish the targeting of the channel to cell junctions. This work describes the first auxiliary subunit of ClC-2 and suggests that ClC-2 may play a role in the pathology of MLC disease.

Original publication

DOI

10.1016/j.neuron.2011.12.039

Type

Journal article

Journal

Neuron

Publication Date

08/03/2012

Volume

73

Pages

951 - 961

Keywords

Animals, Biophysics, Cells, Cultured, Chloride Channels, Connexins, Electric Stimulation, Glial Fibrillary Acidic Protein, Green Fluorescent Proteins, Humans, Immunoprecipitation, Mass Spectrometry, Membrane Potentials, Mice, Mice, Transgenic, Microinjections, Microscopy, Confocal, Microscopy, Electron, Transmission, Models, Molecular, Mutation, Myelin Sheath, Myosin Light Chains, Neuroglia, Oocytes, Patch-Clamp Techniques, Protein Transport, Rats, Transfection, Xenopus