Reversal of charge selectivity in cation or anion-selective epithelial lines by expression of different claudins

Am J Physiol Renal Physiol. 2003 Dec;285(6):F1078-84. doi: 10.1152/ajprenal.00116.2003. Epub 2003 Sep 16.


Tight junctions (TJ) regulate paracellular ionic charge selectivity and conductance across epithelial tissues and cell lines. These properties vary among epithelia, and recent evidence implicates the claudins, a family of TJ transmembrane proteins, as important determinants of both characteristics. To test the hypothesis that each claudin contributes a characteristic charge discrimination to the TJ, we expressed claudins-2, -4, -11, and -15 in both cation-selective Madin-Darby canine kidney (MDCK) II cells and in anion-selective LLC-PK1 cells and examined changes in transepithelial electrical resistance (TER) and paracellular charge selectivity. Regulated expression and localization were verified by immunoblot analysis and immunofluorescence microscopy, respectively. Expression of claudin-4 increased TER in both cell lines, whereas effects of the others on TER were variable. Claudin-4 and -11 decreased paracellular permeability for Na+ in MDCK II cells, whereas neither claudin-2 nor -15 had an effect. Conversely, in LLC-PK1 cells, claudin-2 and -15 increased the permeability for Na+, whereas claudin-4 and -11 were without effect. We conclude that the contribution of each claudin is most easily detectable when it reverses the direction of monolayer charge selectivity. These results are consistent with a model in which exogenous claudins add new charge-selective pores, leading to a physiological phenotype that combines endogenous and exogenous contributions. Additionally, it is possible to rationalize the direction of charge selectivity conferred by the individual claudins on the basis of electrostatic effects of the charged amino acids in their first extracellular loops.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anions / metabolism
  • Cations / metabolism
  • Claudin-4
  • Claudins
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology*
  • Gene Expression
  • Immunohistochemistry
  • Kidney / cytology
  • LLC-PK1 Cells
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Molecular Sequence Data
  • Nerve Tissue Proteins*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Tight Junctions / physiology


  • Anions
  • CLDN2 protein, human
  • CLDN4 protein, human
  • Cations
  • Claudin-4
  • Claudins
  • Cldn11 protein, mouse
  • Cldn2 protein, mouse
  • Cldn4 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • claudin 15
  • Clostridium perfringens enterotoxin receptor