title: Dynamic modulation of ANO1/TMEM16A HCO3(-) permeability by Ca2+/calmodulin.
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.
authors.affiliation: Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Jinsei
authors.initials: J
authors.lastname: Jung
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Nam
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Park
authors.forename: Uhtaek
authors.initials: U
authors.lastname: Oh
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D000818:Animals; D000075369:Anoctamin-1; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000502:physiology*; D018118:Chloride Channels / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018408:Patch-Clamp Techniques; D060888:Real-Time Polymerase Chain Reaction; D013363:Submandibular Gland / Q000166:cytology
chemical_list: C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D001639:Bicarbonates; D002147:Calmodulin; D018118:Chloride Channels; D002118:Calcium