A new Ca²⁺ leak channel

The leucine-rich repeat-containing 8 (LRRC8) proteins bear structural similarities to the channel-forming transmembrane pannexin proteins. LRRC8-members have been identified as part of the volume-regulated anion channel (VRAC), which contributes to volume perturbations in the cell owing to swelling. LRRC8B shows an expression pattern that is similar to that of pannexin, which controls Ca²⁺ homeostasis through the formation of channels in the plasma membrane. In this issue (p. 3818), Amal Kanti Bera and colleagues explore the possibility of Ca²⁺ homeostasis control by LRRC8B. They find that overexpression of LRRC8B in HEK293 cells attenuates the rise of Ca²⁺ that is mediated by ATP-induction and other treatments. Ca²⁺ in the endoplasmic reticulum (ER), the main store of Ca²⁺, is diminished upon LRRC8B overexpression and the authors show that LRRC8B is involved in the leak of calcium from the ER. Furthermore, LRRC8B promotes store-operated Ca²⁺ entry into and associates with the ER in the cell. These data establish LRRC8B as a Ca²⁺ leak channel that is implicated in Ca²⁺ homeostasis in the ER as well as in store-operated Ca²⁺ entry to control basal Ca²⁺ levels and the refill of intracellular Ca²⁺ stores; it also adds a new function to LRRC8 proteins.