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Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC

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Official URL:https://doi.org/10.1126/science.1252826
PubMed:View item in PubMed
Creators Name:Voss, F.K. and Ullrich, F. and Muench, J. and Lazarow, K. and Lutter, D. and Mah, N. and Andrade-Navarro, M.A. and von Kries, J.P. and Stauber, T. and Jentsch, T.J.
Journal Title:Science
Journal Abbreviation:Science
Volume:344
Number:6184
Page Range:634-638
Date:9 May 2014
Keywords:Agammaglobulinemia, Cell Size, Chloride Channels, Gene Knockout Techniques, Genome-Wide Association Study, HCT116 Cells, HEK293 Cells, Membrane Proteins, Mutation, Protein Multimerization, RNA Interference, Small Interfering RNA, Taurine, Transfection
Abstract:Regulation of cell volume is critical for many cellular and organismal functions, yet the molecular identity of a key player, the volume-regulated anion channel VRAC, has remained unknown. A genome-wide siRNA screen in mammalian cells identified LRRC8A as a VRAC component. LRRC8A formed heteromers with other LRRC8 multispan membrane proteins. Genomic disruption of LRRC8A ablated VRAC currents. Cells with disruption of all five LRRC8 genes required LRRC8A co-transfection with other LRRC8 isoforms to reconstitute VRAC currents. The isoform combination determined VRAC inactivation kinetics. Taurine flux and regulatory volume decrease also depended on LRRC8 proteins. Our work shows that VRAC defines a class of anion channels, suggests that VRAC is identical to the volume-sensitive organic osmolyte/anion channel VSOAC, and explains the heterogeneity of native VRAC currents.
ISSN:0036-8075
Publisher:American Association for the Advancement of Science (U.S.A.)
Item Type:Article

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