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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.

Author information

1
Unitat de Fisiologia, Departament de Ciències Fisiològiques, IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
2
Unitat de Genètica, Departament de Ciències Fisiològiques, Laboratori de Genètica Molecular, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
3
Centro de Investigación en Red de Enfermedades Raras (CIBERER), ISCIII.
4
Neurophysiology Laboratory, Physiology Unit, Departament of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
5
Logopharm GmbH, Freiburg, Germany.

Abstract

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.

PMID:
28398517
DOI:
10.1093/hmg/ddx134
[Indexed for MEDLINE]

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