title: Molecular basis for cation selectivity in claudin-2-based paracellular pores: identification of an electrostatic interaction site.
abstract: Paracellular ion transport in epithelia is mediated by pores formed by members of the claudin family. The degree of selectivity and the molecular mechanism of ion permeation through claudin pores are poorly understood. By expressing a high-conductance claudin isoform, claudin-2, in high-resistance Madin-Darby canine kidney cells under the control of an inducible promoter, we were able to quantitate claudin pore permeability. Claudin-2 pores were found to be narrow, fluid filled, and cation selective. Charge selectivity was mediated by the electrostatic interaction of partially dehydrated permeating cations with a negatively charged site within the pore that is formed by the side chain carboxyl group of aspartate-65. Thus, paracellular pores use intrapore electrostatic binding sites to achieve a high conductance with a high degree of charge selectivity.
authors.affiliation: Division of Nephrology, Department of Medicine,University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA. alanyu@usc.edu
authors.forename: Alan S L
authors.initials: AS
authors.lastname: Yu
authors.forename: Mary H
authors.initials: MH
authors.lastname: Cheng
authors.forename: Susanne
authors.initials: S
authors.lastname: Angelow
authors.forename: Dorothee
authors.initials: D
authors.lastname: Günzel
authors.forename: Sanae A
authors.initials: SA
authors.lastname: Kanzawa
authors.forename: Eveline E
authors.initials: EE
authors.lastname: Schneeberger
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
authors.forename: Rob D
authors.initials: RD
authors.lastname: Coalson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002412:Cations / Q000378:metabolism*; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D057167:Claudins; D003198:Computer Simulation; D004285:Dogs; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D055672:Static Electricity
chemical_list: D002412:Cations; D057167:Claudins; C113371:Cldn2 protein, mouse; D007473:Ion Channels; D008565:Membrane Proteins; D020033:Protein Isoforms