5 years ago

Regulation of TMEM16A/ANO1 and TMEM16F/ANO6 ion currents and phospholipid scrambling by Ca(2+) and plasma membrane lipid.

Rainer Schreiber, Jiraporn Ousingsawat, Roberta Benedetto, Podchanart Wanitchakool, Karl Kunzelmann, Lalida Sirianant, Karina Reiss
TMEM16/anoctamin proteins form Ca(2+) activated ion channels or phospholipid scramblases. We found that both TMEM16A/ANO1 and TMEM16F/ANO6 produced Cl(-) currents when activated by intracellular Ca(2+) , but only TMEM16F was able to expose phosphatidylserine to the outer leaflet of the plasma membrane. Mutations within TMEM16F or TMEM16A/F chimeras similarly changed Cl(-) currents and phospholipid scrambling, suggesting the same intramolecular pathway for Cl(-) and phospholipids. When overexpressed, TMEM16A and TMEM16F produced spontaneous Cl(-) currents at 37°C even at resting intracellular Ca(2+) levels, which was abolished by inhibition of phospholipase A2 (PLA2 ). Inversely, activation of PLA2 or application of active PLA2 , as well as lipid peroxidation induced by reactive oxygen species (ROS) using staurosporine or tert-butyl hydroperoxide, enhanced ion currents by TMEM16A/F and in addition activated phospholipid scrambling by TMEM16F. Thus TMEM16 proteins are activated by an increase in intracellular Ca(2+) , or independent of intracellular Ca(2+) by modifications occurring in plasma and intracellular membrane phospholipids. These results may help to understand, why regions distant to the TMEM16 pore and the Ca(2+) binding sites control Cl(-) currents and phospholipid scrambling. Regulation of TMEM16 proteins through modification of membrane phospholipids occurs during regulated cell death such as apoptosis and ferroptosis. It contributes to inflammatory and nerve-injury induced hypersensitivity and generation of pain and therefore provides a regulatory mechanism particularly relevant during disease. This article is protected by copyright. All rights reserved.

Publisher URL: http://doi.org/10.1113/JP275175

DOI: 10.1113/JP275175

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