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GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit

Item Type:Article
Title:GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit
Creators Name:Jeworutzki, E. and Lopez-Hernandez, T. and Capdevila-Nortes, X. and Sirisi, S. and Bengtsson, L. and Montolio, M. and Zifarelli, G. and Arnedo, T. and Mueller, C.S. and Schulte, U. and Nunes, V. and Martinez, A. and Jentsch, T.J. and Gasull, X. and Pusch, M. and Estevez, R.
Abstract: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.
Keywords:Biophysics, Chloride Channels, Confocal Microscopy, Connexins, Cultured Cells, Electric Stimulation, Glial Fibrillary Acidic Protein, Green Fluorescent Proteins, Immunoprecipitation, Mass Spectrometry, Membrane Potentials, Microinjections, Molecular Models, Mutation, Myelin Sheath, Myosin Light Chains, Neuroglia, Oocytes, Patch-Clamp Techniques, Protein Transport, Transgenic Mice, Transmission Electron Microscopy, Transfection, Xenopus, Animals, Mice, Rats
Publisher:Cell Press
Page Range:951-961
Date:8 March 2012
Official Publication:https://doi.org/10.1016/j.neuron.2011.12.039
PubMed:View item in PubMed

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