Centeio, Raquel and Ousingsawat, Jiraporn and Schreiber, Rainer and Kunzelmann, Karl (2020) Ca2+ Dependence of Volume-Regulated VRAC/LRRC8 and TMEM16A Cl- Channels. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 8: 596879. ISSN 2296-634X,
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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 Ca2+-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 Ca2+ release from the endoplasmic reticulum and to cause subsequent Ca2+ influx. It is suggested that TMEM16A/F support intracellular Ca2+ signaling and thus Ca2+-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 Ca2+ dependent. TMEM16A augmented the activation of LRRC8A/C by enhancing swelling-induced local intracellular Ca2+ concentrations. In HT29 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 (IP3R; RyR), as well as by inhibiting Ca2+ influx. The data suggest that TMEM16A contributes directly to I-Cl(,swell) as it is activated through swelling-induced Ca2+ increase. As activation of VRAC is shown to be Ca2+-dependent, TMEM16A augments VRAC currents by facilitating Hypo-induced Ca2+ increase in submembraneous signaling compartments by means of ER tethering.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ANION CHANNELS; ESSENTIAL COMPONENT; INDUCED ACTIVATION; VRAC; EXPRESSION; PHYSIOLOGY; RESPONSES; DEATH; CELLS; ANO1; VRAC; CaCC; TMEM16 proteins; anoctamin; ANO1 |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Mar 2021 07:09 |
| Last Modified: | 08 Mar 2021 07:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43285 |
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