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Cell. 2016 Jan 28;164(3):499-511. doi: 10.1016/j.cell.2015.12.031.

LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength.

Author information

1
Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA.
3
Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: adubin@scripps.edu.
4
Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA.
5
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
6
Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: ardem@scripps.edu.

Abstract

The volume-regulated anion channel (VRAC) is activated when a cell swells, and it plays a central role in maintaining cell volume in response to osmotic challenges. SWELL1 (LRRC8A) was recently identified as an essential component of VRAC. However, the identity of the pore-forming subunits of VRAC and how the channel is gated by cell swelling are unknown. Here, we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of ∼800 kDa. When reconstituted into bilayers, LRRC8 complexes are sufficient to form anion channels activated by osmolality gradients. In bilayers, as well as in cells, the single-channel conductance of the complexes depends on the LRRC8 composition. Finally, low ionic strength (Γ) in the absence of an osmotic gradient activates the complexes in bilayers. These data demonstrate that LRRC8 proteins together constitute the VRAC pore and that hypotonic stress can activate VRAC through a decrease in cytoplasmic Γ.

PMID:
26824658
PMCID:
PMC4733249
DOI:
10.1016/j.cell.2015.12.031
[Indexed for MEDLINE]
Free PMC Article
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