Ca(2+) signals, cell membrane disintegration, and activation of TMEM16F during necroptosis.

Ca(2+) signals, cell membrane disintegration, and activation of TMEM16F during necroptosis.
Cell Mol Life Sci. 2016 Aug 17;
Authors: Ousingsawat J, Cabrita I, Wanitchakool P, Sirianant L, Krautwald S, Linkermann A, Schreiber R, Kunzelmann K
Abstract
Activated receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain like (MLKL) are essential components of the necroptotic pathway. Phosphorylated MLKL (pMLKL) is thought to induce membrane leakage, leading to cell swelling and disintegration of the cell membrane. However, the molecular identity of the necroptotic membrane pore remains unclear, and the role of pMLKL for membrane permeabilization is currently disputed. We observed earlier that the phospholipid scramblase and ion channel TMEM16F/anoctamin 6 cause large membrane currents, cell swelling, and cell death when activated by a strong increase in intracellular Ca(2+). We, therefore, asked whether TMEM16F is also central to necroptotic cell death and other cellular events during necroptosis. Necroptosis was induced by TNFα, smac mimetic, and Z-VAD (TSZ) in NIH3T3 fibroblasts and the four additional cell lines HT29, 16HBE, H441, and L929. Time-dependent changes in intracellular Ca(2+), cell morphology, and membrane currents were recorded. TSZ induced a small and only transient oscillatory rise in intracellular Ca(2+), which was paralleled by the activation of outwardly rectifying Cl(-) currents, which were typic...

Source: Cellular and Molecular Life Sciences : CMLS - August 16, 2016 Category: Cytology Authors: Ousingsawat J, Cabrita I, Wanitchakool P, Sirianant L, Krautwald S, Linkermann A, Schreiber R, Kunzelmann K Tags: Cell Mol Life Sci Source Type: research