title: Pore dilatation increases the bicarbonate permeability of CFTR, ANO1 and glycine receptor anion channels.
abstract: Cellular stimuli can modulate the ion selectivity of some anion channels, such as CFTR, ANO1 and the glycine receptor (GlyR), by changing pore size. Ion selectivity of CFTR, ANO1 and GlyR is critically affected by the electric permittivity and diameter of the channel pore. Pore size change affects the energy barriers of ion dehydration as well as that of size-exclusion of anion permeation. Pore dilatation increases the bicarbonate permeability (P HC O3/ Cl ) of CFTR, ANO1 and GlyR. Dynamic change in P HC O3/ Cl may mediate many physiological and pathological processes.
  
  
  
  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.
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.|Department of Ophthalmology, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Ikhyun
authors.initials: I
authors.lastname: Jun
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mary Hongying
authors.initials: MH
authors.lastname: Cheng
authors.affiliation: Department of Chemistry, Yonsei University College of Science, Seoul, 120-749, Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Sim
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.|Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Jinsei
authors.initials: J
authors.lastname: Jung
authors.affiliation: Department of Chemistry, Yonsei University College of Science, Seoul, 120-749, Korea.
authors.forename: Bong Lim
authors.initials: BL
authors.lastname: Suh
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Yonjung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Hankil
authors.initials: H
authors.lastname: Son
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Whitcomb
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000075369:Anoctamin-1; D001639:Bicarbonates / Q000378:metabolism*; D018118:Chloride Channels / Q000737:chemistry / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D022022:Nuclear Pore / Q000378:metabolism*; D010539:Permeability; D017434:Protein Structure, Tertiary; D018009:Receptors, Glycine / Q000737:chemistry / Q000378:metabolism*
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D001639:Bicarbonates; C505032:CFTR protein, human; D018118:Chloride Channels; D009363:Neoplasm Proteins; D018009:Receptors, Glycine; D019005:Cystic Fibrosis Transmembrane Conductance Regulator