Cellular volume regulation by anoctamin 6: Ca²⁺, phospholipase A2 and osmosensing

Pflugers Arch. 2016 Feb;468(2):335-49. doi: 10.1007/s00424-015-1739-8. Epub 2015 Oct 6.


During cell swelling, Cl(-) channels are activated to lower intracellular Cl(-) concentrations and to reduce cell volume, a process termed regulatory volume decrease (RVD). We show that anoctamin 6 (ANO6; TMEM16F) produces volume-regulated anion currents and controls cell volume in four unrelated cell types. Volume regulation is compromised in freshly isolated intestinal epithelial cells from Ano6-/- mice and also in lymphocytes from a patient lacking expression of ANO6. Ca(2+) influx is activated and thus ANO6 is stimulated during cell swelling by local Ca(2+) increase probably in functional nanodomains near the plasma membrane. This leads to stimulation of phospholipase A2 (PLA2) and generation of plasma membrane lysophospholipids, which activates ANO6. Direct application of lysophospholipids also activates an anion current that is inhibited by typical ANO6 blocker. An increase in intracellular Ca(2+) supports activation of ANO6, but is not required when PLA2 is fully activated, while re-addition of arachidonic acid completely blocked ANO6. Moreover, ANO6 is activated by low intracellular Cl(-) concentrations and may therefore operate as a cellular osmosensor. High intracellular Cl(-) concentration inhibits ANO6 and activation by PLA2. Taken together, ANO6 supports volume regulation and volume activation of anion currents by action as a Cl(-) channel or by scrambling membrane phospholipids. Thereby, it may support the function of LRRC8 proteins.

Keywords: Anoctamin 6; Apoptosis; RVD; Regulatory volume decrease; TMEM16F; VRAC; Volume regulation; Volume-regulated anion channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Anoctamins
  • Calcium Signaling*
  • Cell Size*
  • Cells, Cultured
  • Chlorides / metabolism
  • HEK293 Cells
  • Humans
  • Lymphocytes / cytology
  • Lymphocytes / metabolism*
  • Lysophospholipids / metabolism
  • Mice
  • Oocytes
  • Osmoregulation*
  • Phospholipases A2 / metabolism*
  • Phospholipid Transfer Proteins / antagonists & inhibitors
  • Phospholipid Transfer Proteins / genetics
  • Phospholipid Transfer Proteins / metabolism*


  • ANO6 protein, mouse
  • Anoctamins
  • Chlorides
  • Lysophospholipids
  • Phospholipid Transfer Proteins
  • Phospholipases A2