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All vertebrate cells activate Cl –  currents (I Cl  ,swell ) when swollen by hypotonic bath solution. The volume-regulated anion channel VRAC has now been identified as LRRC8/SWELL1. However, apart from VRAC, the Ca 2+ -activated Cl –  channel (CaCC) TMEM16A and the phospholipid scramblase and ion channel TMEM16F were suggested to contribute to cell swelling-activated whole-cell currents. Cell swelling was shown to induce Ca 2+  release from the endoplasmic reticulum and to cause subsequent Ca 2+  influx. It is suggested that TMEM16A/F support intracellular Ca 2+  signaling and thus Ca 2+ -dependent activation of VRAC. In the present study, we tried to clarify the contribution of TMEM16A to I Cl  ,swell . In HEK293 cells coexpressing LRRC8A and LRRC8C, we found that activation of I Cl  ,swell  by hypotonic bath solution (Hypo; 200 mosm/l) was Ca 2+  dependent. TMEM16A augmented the activation of LRRC8A/C by enhancing swelling-induced local intracellular Ca 2+  concentrations. In HT 29  cells, knockdown of endogenous TMEM16A attenuated I Cl  ,swell  and changed time-independent swelling-activated currents to VRAC-typical time-dependent currents. Activation of I Cl  ,swell  by Hypo was attenuated by blocking receptors for inositol trisphosphate and ryanodine (IP 3 R; RyR), as well as by inhibiting Ca 2+  influx. The data suggest that TMEM16A contributes directly to I Cl  ,swell  as it is activated through swelling-induced Ca 2+  increase. As activation of VRAC is shown to be Ca 2+ -dependent, TMEM16A augments VRAC currents by facilitating Hypo-induced Ca 2+  increase in submembraneous signaling compartments by means of ER tethering.

Ca2+ Dependence of Volume-Regulated VRAC/LRRC8 and TMEM16A Cl– Channels