GlialCAM/MLC1 modulates LRRC8/VRAC currents in an indirect manner: Implications for megalencephalic leukoencephalopathy.

GlialCAM/MLC1 modulates LRRC8/VRAC currents in an indirect manner: Implications for megalencephalic leukoencephalopathy. Neurobiol Dis. 2018 Aug 01;119:88-99 Authors: Elorza-Vidal X, Sirisi S, Gaitán-Peñas H, Pérez-Rius C, Alonso-Gardón M, Armand-Ugón M, Lanciotti A, Brignone MS, Prat E, Nunes V, Ambrosini E, Gasull X, Estévez R Abstract Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM genes. Previous work indicated that chloride currents mediated by the volume-regulated anion channel (VRAC) and ClC-2 channels were affected in astrocytes deficient in either Mlc1 or Glialcam. ClC-2 forms a ternary complex with GlialCAM and MLC1. LRRC8 proteins have been identified recently as the molecular components of VRAC, but the relationship between MLC and LRRC8 proteins is unknown. Here, we first demonstrate that LRRC8 and MLC1 are functionally linked, as MLC1 cannot potentiate VRAC currents when LRRC8A, the main subunit of VRAC, is knocked down. We determine that LRRC8A and MLC1 do not co-localize or interact and, in Xenopus oocytes, MLC1 does not potentiate LRRC8-mediated VRAC currents, indicating that VRAC modulation in astrocytes by MLC1 may be indirect. Investigating the mechanism of modulation, we find that a lack of MLC1 does not influence either mRNA or total and plasma membrane protein levels of LRRC8A; and neither does it affect LRRC8...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research