Claudins create charge-selective channels in the paracellular pathway between epithelial cells

Oscar R. Colegio, Christina M. Van Itallie, Heather J. McCrea, Christoph Rahner, James Melvin Anderson

Research output: Contribution to journalArticlepeer-review

402 Scopus citations


Epithelia separate tissue spaces by regulating the passage of ions, solutes, and water through both the transcellular and paracellular pathways. Paracellular permeability is defined by intercellular tight junctions, which vary widely among tissues with respect to solute flux, electrical resistance, and ionic charge selectivity. To test the hypothesis that members of the claudin family of tight junction proteins create charge selectivity, we assessed the effect of reversing the charge of selected extracellular amino acids in two claudins using site-directed mutagenesis. Claudins were expressed in cultured Madin-Darby canine kidney cell monolayers under an inducible promoter, and clones were compared with and without induction for transmonolayer electrical resistance and dilution potentials. Expression and localization of claudins were determined by immunoblotting, immunofluorescence microscopy, and freeze-fracture electron microscopy. We observed that substituting a negative for a positive charge at position 65 in the first extracellular domain of claudin-4 increased paracellular Na+ permeability. Conversely, substituting positive for negative charges at three positions in the first extracellular domain of claudin-15, singly and in combination, reversed paracellular charge selectivity from a preference for Na+ to Cl-. These results support a model where claudins create charge-selective channels in the paracellular space.

Original languageEnglish (US)
Pages (from-to)C142-C147
JournalAmerican Journal of Physiology - Cell Physiology
Issue number1 52-1
StatePublished - 2002
Externally publishedYes


  • Claudin-15
  • Claudin-4
  • Dilution potential
  • Intercellular junction
  • Tight junction

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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