SWELL1, a Plasma Membrane Protein, Is an Essential Component of Volume-Regulated Anion Channel
Open accessAbstract
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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There is evidence that glucose may activate the volume-regulated anion (VRAC) Cl- channel, and VRAC was recently identified as LRRC8A, which is expressed at low but detectable levels in both mouse and human β-cells.
“There is evidence that glucose may activate the volume-regulated anion (VRAC) Cl- channel (65, 349). VRAC was recently identified as the ‘leucine-rich repeats containing 8A’ protein (Lrrc8a/LRRC8A) (527, 713), which is expressed at low but detectable levels in both mouse and human β-cells (3, 68, 146, 475).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [527]
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- Authors
- Qiu, Z., Dubin, A. E., Mathur, J., Tu, B., Reddy, K., Miraglia, L. J., Reinhardt, J., Orth, A. P., & Patapoutian, A.
- Affiliations
- Scripps Research Institute (US)
- Genomics Institute of the Novartis Research Foundation (US)
- Novartis (Switzerland) (CH)
- Corresponding author
- Patapoutian, Ardem
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 157
- Issue
- 2
- Pages
- 447-458
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4023864
- OpenAlex
- W2076968934
- Cited by
- 571
- References
- 0
- Citations by year
- 2026: 35 · 2025: 45 · 2024: 46 · 2023: 49 · 2022: 62 · 2021: 58 · 2020: 36 · 2019: 59 · 2018: 46 · 2017: 32 · 2016: 41 · 2015: 37 · 2014: 25
- FWCI
- 18.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Dental and Craniofacial Research (R01DE022115)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- LRRC8A, volume-regulated anion channel, cell volume regulation, osmotic balance, plasma membrane proteins, anion selectivity, genome-wide RNAi screen
- MeSH terms
- Animals, Cell Membrane, HeLa Cells, Humans, Iodides, Membrane Proteins, Gene Expression Profiling, RNA Interference, Cell Size, Mice, Genome-Wide Association Study, Gene Knockdown Techniques, HEK293 Cells
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