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

Ruhma Syeda, Zhaozhu Qiu, Adrienne E. Dubin, Swetha E. Murthy, Maria N. Florendo, Daniel E. Mason, Jayanti Mathur, Stuart M. Cahalan, Eric C. Peters, Mauricio Montal, Ardem Patapoutian

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)499-511
Number of pages13
JournalCell
Volume164
Issue number3
DOIs
StatePublished - Jan 28 2016

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Syeda, R., Qiu, Z., Dubin, A. E., Murthy, S. E., Florendo, M. N., Mason, D. E., Mathur, J., Cahalan, S. M., Peters, E. C., Montal, M., & Patapoutian, A. (2016). LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength. Cell, 164(3), 499-511. https://doi.org/10.1016/j.cell.2015.12.031