Jinsei Junga,b, Joo Hyun Namc, Hyun Woo Parka, Uhtaek Ohd, Joo-Heon Yoonb, and Min Goo Leea,1
aDepartment of Pharmacology, Brain Korea 21 Project for Medical Sciences, and
bDepartment of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 120-752, Korea;
cDepartment of Physiology, College of Medicine, Dongguk University, Gyeongju 780-714, Korea; and
dSensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Edited by Richard W. Aldrich, University of Texas, Austin, TX, and approved November 19, 2012 (received for review July 7, 2012)
Anoctamin 1 (ANO1)/transmembrane protein 16A (TMEM16A) is a calcium-activated anion channel that may play a role in HCO3- secretion in epithelial cells. Here, we report that the anion selectivity of ANO1 is dynamically regulated by the Ca2+/calmodulin complex. Whole-cell current measurements in HEK 293T cells indicated that ANO1 becomes highly permeable to HCO3- at high [Ca2+]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 [Ca2+]i is responsible for changes in anion permeability. Calmodulin physically interacted with ANO1 in a [Ca2+]i-dependent manner, and addition of recombinant calmodulin to the cytosolic side of excised patches reversibly increased PHCO3/PCl. In addition, the high [Ca2+]i-induced increase in HCO3- permeability was reproduced in mouse submandibular gland acinar cells, in which ANO1 plays a critical role in fluid secretion. These results indicate that the HCO3- permeability of ANO1 can be dynamically modulated and that ANO1 may play an important role in cellular HCO3- transport, especially in transepithelial HCO3- secretion.
1To whom correspondence should be addressed.
Author contributions: M.G.L. designed research; J.J., J.H.N., and H.W.P. performed research; U.O. and J.-H.Y. contributed new reagents/analytic tools; J.J. and M.G.L. analyzed data; and J.J. and M.G.L. wrote the paper.