title: Effects of Cd2+ on the epithelial Na+ channel (ENaC) investigated by experimental and modeling studies.
abstract: The function of the epithelial Na+ channel from the apical membrane of many Na+ transporting epithelia is modulated by various chemical compounds from the extracellular space, such as heavy metals, protons or chloride ions. We have studied the effect of extracellular Cd2+ on the function of the epithelial Na+ channel (ENaC) in heterologously expressed Xenopus laevis oocytes and Na+-transporting epithelia. We assayed channel function as the amiloride-sensitive sodium current (I(Na)). Cd2+ rapidly and voltage-independently inhibited INa in oocytes expressing αβγ Xenopus ENaC (xENaC). The extracellular Cd2+ inhibited Na+ transport and showed no influence on ENaC trafficking, as revealed by concomitant measurements of the transepithelial current, conductance and capacitance in Na+-transporting epithelia. Instead, amiloride inhibition was noticeably diminished in the presence of Cd2+ on the apical membrane. Using molecular modeling approaches, we describe the amiloride binding sites in rat and xENaC structures, and we present four putative binding sites for Cd2+. These results indicate that ENaC functions as a sensor for external Cd2+.
authors.affiliation: Department of Anatomy, Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania. dana.cucu@bio.unibuc.ro.
authors.forename: Maria
authors.initials: M
authors.lastname: Mernea
authors.forename: Roxana
authors.initials: R
authors.lastname: Ulăreanu
authors.forename: Octavian
authors.initials: O
authors.lastname: Călborean
authors.forename: Sergiu
authors.initials: S
authors.lastname: Chira
authors.forename: Octavian
authors.initials: O
authors.lastname: Popescu
authors.forename: Dan F
authors.initials: DF
authors.lastname: Mihailescu
authors.forename: Dana
authors.initials: D
authors.lastname: Cucu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002104:Cadmium / Q000008:administration & dosage*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053503:Epithelial Sodium Channels / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding; D012964:Sodium / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D053503:Epithelial Sodium Channels; D002104:Cadmium; D012964:Sodium