title: Alveolar nonselective channels are ASIC1a/α-ENaC channels and contribute to AFC.
abstract: A thin fluid layer in alveoli is normal and results from a balance of fluid entry and fluid uptake by transepithelial salt and water reabsorption. Conventional wisdom suggests the reabsorption is via epithelial Na+channels (ENaC), but if all Na+reabsorption were via ENaC, then amiloride, an ENaC inhibitor, should block alveolar fluid clearance (AFC). However, amiloride blocks only half of AFC. The reason for failure to block is clear from single-channel measurements from alveolar epithelial cells: ENaC channels are observed, but another channel is present at the same frequency that is nonselective for Na+over K+, has a larger conductance, and has shorter open and closed times. These two channel types are known as highly selective channels (HSC) and nonselective cation channels (NSC). HSC channels are made up of three ENaC subunits since knocking down any of the subunits reduces HSC number. NSC channels contain α-ENaC since knocking down α-ENaC reduces the number of NSC (knocking down β- or γ-ENaC has no effect on NSC, but the molecular composition of NSC channels remains unclear). We show that NSC channels consist of at least one α-ENaC and one or more acid-sensing ion channel 1a (ASIC1a) proteins. Knocking down either α-ENaC or ASIC1a reduces both NSC and HSC number, and no NSC channels are observable in single-channel patches on lung slices from ASIC1a knockout mice. AFC is reduced in knockout mice, and wet wt-to-dry wt ratio is increased, but the percentage increase in wet wt-to-dry wt ratio is larger than expected based on the reduction in AFC.
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Phi T
authors.initials: PT
authors.lastname: Trac
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Thai
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Valerie
authors.initials: V
authors.lastname: Linck
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Li
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Megan
authors.initials: M
authors.lastname: Greenlee
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yue
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Otor
authors.initials: O
authors.lastname: Al-Khalili
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Alli
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Amity F
authors.initials: AF
authors.lastname: Eaton
authors.affiliation: Department of Physiology and Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia; and deaton@emory.edu.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Eaton
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002478:Cells, Cultured; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010100:Oxygen / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism*; D012910:Snake Venoms / Q000633:toxicity; D014867:Water / Q000378:metabolism
chemical_list: D062565:Acid Sensing Ion Channels; D053503:Epithelial Sodium Channels; D021122:Protein Subunits; D012910:Snake Venoms; D014867:Water; D010100:Oxygen
keywords: acid-sensing ion channel 1a; alveolar fluid clearance; alveoli; lung fluid balance; nonselective cation channels; α-epithelial Na+ channels