Chloride (Cl-) and bicarbonate (HCO3-) are two major anions and their permeation through anion channels plays essential roles in our body. However, the mechanism of ion selection by the anion channels is largely unknown. Here, we provide evidence that pore dilatation increases the bicarbonate permeability (P HC O3/ Cl ) of anion channels by reducing energy barriers of size-exclusion and ion dehydration of HCO3- permeation. Molecular, physiological and computational analyses of major anion channels, such as cystic fibrosis transmembrane conductance regulator (CFTR), anoctamin-1(ANO1/TMEM16A) and the glycine receptor (GlyR), revealed that the ion selectivity of anion channels is basically determined by the electric permittivity and diameter of the pore. Importantly, cellular stimuli dynamically modulate the anion selectivity of CFTR and ANO1 by changing the pore size. In addition, pore dilatation by a mutation in the pore-lining region alters the anion selectivity of GlyR. Changes in pore size affected not only the energy barriers of size exclusion but that of ion dehydration by altering the electric permittivity of water-filled cavity in the pore. The dynamic increase in P HC O3/ Cl by pore dilatation may have many physiological and pathophysiological implications ranging from epithelial HCO3- secretion to neuronal excitation.
Bibliographical noteFunding Information:
This work was supported by grants 2013R1A3A2042197 (M.G.L.), 2007‐0056092 (M.G.L.) and 2014R1A1A3049671 (E.S.) from the National Research Foundation, the Ministry of Science, ICT & Future Planning, and grant HI14C0070 (M.G.L.) from the Korea Health Technology R&D Project, KHIDI, the Ministry of Health & Welfare, Republic of Korea. M.C. and I.B. gratefully acknowledge financial support by NIH P30 DA035778, 5R01 GM099738‐04 and P41 GM103712.
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