Regulation of ANO1/TMEM16A anion permeability

Abstract

Background/aim: Bicarbonate (HCO3 ) is an important ingredient in many biological fluids including saliva. However, calcium activated chlo ride channels (CaCCs) in salivary gland acinar cells are known to be poorly permeable to HCO3 in most cases. Methods: To elucidate the possibility of ANO1 as a HCO3 channel, anion currents were measured in HEK 293T cells transfected with human ANO1 (ac isoform) using the whole cell patch clamp techniques. Results: Relative permeabilities of HCO3 and various other anions were altered by high cytosolic calcium signals inwhole cell patch clamp. Further studies including biochemical and excised patch experiments revealed that a direct association between ANO1 and calmodulin at high [Ca2þ]i and an increase in the dielectric constant of ANO1 anion selectivity filter are responsible for changes in anion permeability. In addition, the high [Ca2þ]i induced increase in HCO3 permeability was reproduced in mouse sub mandibular gland acinar cells, in which ANO1 plays a critical role in fluid secretion. Conclusions: Anion selectivity in ANO1 is dynamically regulated by Ca2þ/calmodulin.