title: GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit.
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.
authors.affiliation: Istituto di Biofisica, Consiglio Nazionale delle Ricerche, 16149 Genoa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Jeworutzki
authors.forename: Tania
authors.initials: T
authors.lastname: López-Hernández
authors.forename: Xavier
authors.initials: X
authors.lastname: Capdevila-Nortes
authors.forename: Sònia
authors.initials: S
authors.lastname: Sirisi
authors.forename: Luiza
authors.initials: L
authors.lastname: Bengtsson
authors.forename: Marisol
authors.initials: M
authors.lastname: Montolio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zifarelli
authors.forename: Tanit
authors.initials: T
authors.lastname: Arnedo
authors.forename: Catrin S
authors.initials: CS
authors.lastname: Müller
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulte
authors.forename: Virginia
authors.initials: V
authors.lastname: Nunes
authors.forename: Albert
authors.initials: A
authors.lastname: Martínez
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
authors.forename: Xavier
authors.initials: X
authors.lastname: Gasull
authors.forename: Michael
authors.initials: M
authors.lastname: Pusch
authors.forename: Raúl
authors.initials: R
authors.lastname: Estévez
mesh_terms: D000818:Animals; D001703:Biophysics; D000090007:CLC-2 Chloride Channels; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D017630:Connexins / Q000378:metabolism; D004558:Electric Stimulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections / Q000379:methods; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D018994:Myosin Light Chains / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism* / Q000648:ultrastructure; D009865:Oocytes; D018408:Patch-Clamp Techniques; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D014162:Transfection; D014981:Xenopus
chemical_list: D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; D017630:Connexins; D005904:Glial Fibrillary Acidic Protein; D018994:Myosin Light Chains; C076659:myosin light chain I; D049452:Green Fluorescent Proteins