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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/220715
LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
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Regulation of cell volume is essential for tissue homeostasis and cell viability. In response to hypertonic stress, cells need rapid electrolyte influx to compensate water loss and to prevent cell death in a process known as regulatory volume increase (RVI). However, the molecular component able to trigger such a process was unknown to date. Using a genome-wide CRISPR/Cas9 screen, we identified LRRC8A, which encodes a chloride channel subunit, as the gene most associated with cell survival under hypertonic conditions. Hypertonicity activates the p38 stress-activated protein kinase pathway and its downstream MSK1 kinase, which phosphorylates and activates LRRC8A. LRRC8Amediated Cl− efflux facilitates activation of the with-no-lysine (WNK) kinase pathway, which in turn, promotes electrolyte influx via Na+/K+/ 2Cl− cotransporter (NKCC) and RVI under hypertonic stress. LRRC8AS217A mutation impairs channel activation by MSK1, resulting in reduced RVI and cell survival. In summary, LRRC8A is key to bidirectional osmotic stress responses and cell survival under hypertonic conditions.
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SERRA, Selma a., STOJAKOVIC, Predrag, AMAT, Ramon, RUBIO MOSCARDO, Fanny, LATORRE DOMENECH, Pablo, SEISENBACHER, Gerhard, CANADELL SALA, David, BÖTTCHER, René, AREGGER, Michael, MOFFAT, Jason, NADAL CLANCHET, Eulàlia de, VALVERDE, Miguel a., POSAS, Francesc. LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions. _Proceedings of the National Academy of Sciences of the United States of America_. 2021. Vol. 118, núm. 23. [consulta: 22 de gener de 2026]. ISSN: 1091-6490. [Disponible a: https://hdl.handle.net/2445/220715]