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Hum Mol Genet. 2017 Jul 1;26(13):2436-2450. doi: 10.1093/hmg/ddx134.

Depolarization causes the formation of a ternary complex between GlialCAM, MLC1 and ClC-2 in astrocytes: implications in megalencephalic leukoencephalopathy.

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Unitat de Fisiologia, Departament de Ciències Fisiològiques, IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Unitat de Genètica, Departament de Ciències Fisiològiques, Laboratori de Genètica Molecular, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Centro de Investigación en Red de Enfermedades Raras (CIBERER), ISCIII.
Neurophysiology Laboratory, Physiology Unit, Departament of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
Logopharm GmbH, Freiburg, Germany.


Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM. GlialCAM is necessary for the correct targeting of MLC1, but also for the targeting of the Cl- channel ClC-2. Furthermore, GlialCAM modifies ClC-2 functional properties in vitro. However, in vivo studies in GlialCAM-/- mice have shown that the modification of ClC-2 activity only occurs in oligodendrocytes, despite GlialCAM and ClC-2 being expressed in astrocytes. Thus, the relationship between GlialCAM, MLC1 and ClC-2 in astrocytes is unknown. Here, we show that GlialCAM, ClC-2 and MLC1 can form a ternary complex in cultured astrocytes, but only under depolarizing conditions. We also provide biochemical evidences that this ternary complex exists in vivo. The formation of this complex changes ClC-2 localization in the membrane and its functional properties. ClC-2 association with GlialCAM/MLC1 depends on calcium flux through L-type calcium channels and activation of calcium-dependent calpain proteases. Based on these studies, we propose that the chloride influx mediated by GlialCAM/MLC1/ClC-2 in astrocytes may be needed to compensate an excess of potassium, as occurs in conditions of high neuronal activity. We suggest that a defect in this compensation may contribute to the pathogenesis of MLC disease.

[Indexed for MEDLINE]

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