Anoctamins are a family of Ca2+-activated Cl- channels

J Cell Sci. 2012 Nov 1;125(Pt 21):4991-8. doi: 10.1242/jcs.109553. Epub 2012 Sep 3.

Abstract

Anoctamin 1 (Ano1; TMEM16A) and anoctamin 2 (Ano2; TMEM16B) are novel Cl(-) channels transiently activated by an increase in intracellular Ca(2+). These channels are essential for epithelial Cl(-) secretion, smooth muscle peristalsis and olfactory signal transduction. They are central to inherited diseases and cancer and can act as heat sensors. Surprisingly, another member of this protein family, Ano6, operates as a Ca(2+)-activated phospholipid scramblase, and others were reported as intracellular proteins. It is therefore unclear whether anoctamins constitute a family of Ca(2+)-activated Cl(-) channels, or are proteins with heterogeneous functions. Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. Although some anoctamins (Ano1, 2, 4, 6, 7) were found to be well expressed in the plasma membrane, others (Ano8, 9, 10) show rather poor membrane expression and were mostly retained in the cytosol. The transient nature of the Cl(-) currents was demonstrated to be independent of intracellular Ca(2+) levels. We show that inactivation of Ano1 currents occurs in the continuous presence of elevated Ca(2+) concentrations, possibly by calmodulin-dependent kinase. The present results demonstrate that anoctamins are a family of Ca(2+)-activated Cl(-) channels, which also induce permeability for cations. They may operate as Cl(-) channels located in the plasma membrane or in intracellular compartments. These results increase our understanding of the physiological significance of anoctamins and their role in disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / physiology
  • Anoctamin-1
  • Anoctamins
  • Calcium / metabolism
  • Calcium / physiology
  • Calcium Ionophores / pharmacology
  • Calcium Signaling
  • Cell Membrane / metabolism
  • Cell Membrane Permeability
  • Chloride Channels / metabolism*
  • Chloride Channels / physiology
  • Cytoplasm / metabolism
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Ionomycin / pharmacology
  • Membrane Potentials
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Molecular Sequence Annotation
  • Neoplasm Proteins / metabolism*
  • Neoplasm Proteins / physiology
  • Patch-Clamp Techniques
  • Phospholipid Transfer Proteins / metabolism*
  • Phospholipid Transfer Proteins / physiology
  • Protein Transport

Substances

  • ANO1 protein, human
  • ANO7 protein, human
  • Ano6 protein, human
  • Anoctamin-1
  • Anoctamins
  • Calcium Ionophores
  • Chloride Channels
  • Membrane Proteins
  • Neoplasm Proteins
  • Phospholipid Transfer Proteins
  • Ionomycin
  • Adenosine Triphosphate
  • Calcium