LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
Selma A. Serra, Predrag Stojakovic, Ramon Amat, Fanny Rubio-Moscardó, Pablo Latorre, Gerhard Seisenbacher, David Canadell, René Böttcher, Michael Aregger, Jason Moffat, Eulàlia de Nadal, Miguel A. Valverde, Francesc Posas
Abstract
Significance Rapid regulatory volume increase (RVI) is important for cell survival under hypertonic conditions. RVI is driven by Cl − uptake via the Na–K–Cl cotransporter (NKCC), which is activated by WNK kinases following a reduction in intracellular [Cl − ]. However, how intracellular [Cl − ] is regulated to modulate the WNK–NKCC axis and engage a protective RVI remains unknown. Our work reveals that LRRC8A-containing chloride channel is a key protective factor against hypertonic shocks. Considering that LRRC8A (SWELL1) is typically activated by low ionic strength under hypotonic stress, our results posed another interesting question: what activates this chloride channel under hypertonic stress? We demonstrated that, upon hyperosmotic activation, the p38-MSK1 pathway gates LRRC8A-containing chloride channel to facilitate activation of WNK–NKCC and an effective RVI.