Identification of LRRC8 Heteromers as an Essential Component of the Volume-Regulated Anion Channel VRAC

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Science  09 May 2014:
Vol. 344, Issue 6184, pp. 634-638
DOI: 10.1126/science.1252826

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One Swell Ion Channel

When mammalian cells are faced with osmotic challenges, they need to swell or shrink. The molecular characterization of the volume-regulated anion channel (VRAC) remains unknown, although many candidate proteins have been proposed. Voss et al. (p. 634, published online 10 April; see the Perspective by Mindell) used a genome-wide screen to identify a group of leucine-rich repeat–containing (LRRC) proteins necessary for forming VRAC. Suppression of LRRC8A nearly eliminated the presence of VRAC in mammalian cells. A heterooligomer of LRRC proteins appears to form VRAC. Identification of VRAC components is an essential step forward in the understanding of swelling-activated ion channels and provides opportunities for understanding both the mechanism of the channel and its role in physiology.


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 small interfering RNA 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 cotransfection 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.

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