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Cell. 2014 Apr 10;157(2):447-458. doi: 10.1016/j.cell.2014.03.024.

SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel.

Author information

1
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA; Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
4
Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
5
Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: ardem@scripps.edu.

Abstract

Maintenance of a constant cell volume in response to extracellular or intracellular osmotic changes is critical for cellular homeostasis. Activation of a ubiquitous volume-regulated anion channel (VRAC) plays a key role in this process; however, its molecular identity in vertebrates remains unknown. Here, we used a cell-based fluorescence assay and performed a genome-wide RNAi screen to find components of VRAC. We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. Furthermore, point mutations in SWELL1 cause a significant change in VRAC anion selectivity, demonstrating that SWELL1 is an essential VRAC component. These findings enable further molecular characterization of the VRAC channel complex and genetic studies for understanding the function of VRAC in normal physiology and disease.

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PMID:
24725410
PMCID:
PMC4023864
DOI:
10.1016/j.cell.2014.03.024
[Indexed for MEDLINE]
Free PMC Article
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