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      Dynamic modulation of ANO1/TMEM16A HCO3(-) permeability by Ca2+/calmodulin.

      Proceedings of the National Academy of Sciences of the United States of America

      Acinar Cells, metabolism, Animals, Bicarbonates, Calcium, Calmodulin, Cell Membrane Permeability, physiology, Chloride Channels, Epithelial Cells, HEK293 Cells, Humans, Immunoblotting, Mice, Patch-Clamp Techniques, Real-Time Polymerase Chain Reaction, Submandibular Gland, cytology

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          Abstract

          Anoctamin 1 (ANO1)/transmembrane protein 16A (TMEM16A) is a calcium-activated anion channel that may play a role in HCO(3)(-) secretion in epithelial cells. Here, we report that the anion selectivity of ANO1 is dynamically regulated by the Ca(2+)/calmodulin complex. Whole-cell current measurements in HEK 293T cells indicated that ANO1 becomes highly permeable to HCO(3)(-) at high [Ca(2+)](i). Interestingly, this result was not observed in excised patches, indicating the involvement of cytosolic factors in this process. Further studies revealed that the direct association between ANO1 and calmodulin at high [Ca(2+)](i) is responsible for changes in anion permeability. Calmodulin physically interacted with ANO1 in a [Ca(2+)](i)-dependent manner, and addition of recombinant calmodulin to the cytosolic side of excised patches reversibly increased P(HCO3)/P(Cl). In addition, the high [Ca(2+)](i)-induced increase in HCO(3)(-) permeability was reproduced in mouse submandibular gland acinar cells, in which ANO1 plays a critical role in fluid secretion. These results indicate that the HCO(3)(-) permeability of ANO1 can be dynamically modulated and that ANO1 may play an important role in cellular HCO(3)(-) transport, especially in transepithelial HCO(3)(-) secretion.

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          Author and article information

          Journal
          23248295
          3538232
          10.1073/pnas.1211594110

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