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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cell Size*
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Genome-Wide Association Study
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Iodides / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • RNA Interference


  • Iodides
  • LRRC8A protein, human
  • Membrane Proteins