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Molecular and Cellular Biology, October 2004, p. 8408-8417, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8408-8417.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Selective Decrease in Paracellular Conductance of Tight Junctions: Role of the First Extracellular Domain of Claudin-5

Huajie Wen, Debbie D. Watry, M. Cecilia G. Marcondes, and Howard S. Fox*

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Received 3 February 2004/ Returned for modification 17 March 2004/ Accepted 29 June 2004

Claudin-5 is a protein component of many endothelial tight junctions, including those at the blood-brain barrier, a barrier that limits molecular exchanges between the central nervous system and the circulatory system. To test the contribution of claudin-5 to this barrier function of tight junctions, we expressed murine claudin-5 in Madin-Darby canine kidney II cells. The result was a fivefold increase in transepithelial resistance in claudin-5 transductants and a reduction in conductance of monovalent cations. However, the paracellular flux of neither neutral nor charged monosaccharides was significantly changed in claudin-5 transductants compared to controls. Therefore, expression of claudin-5 selectively decreased the permeability to ions. Additionally, site-directed mutations of particular amino acid residues in the first extracellular domain of claudin-5 altered the properties of the tight junctions formed in response to claudin-5 expression. In particular, the conserved cysteines were crucial: mutation of either cysteine abolishted the ability of claudin-5 to increase transepithelial resistance, and mutation of Cys64 strikingly increased the paracellular flux of monosaccharides. These new insights into the functions of claudin-5 at the molecular level in tight junctions may account for some aspects of the blood-brain barrier's selective permeability.

* Corresponding author. Mailing address: Mailstop CVN-1, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-7171. Fax: (858) 784-7296. E-mail: hsfox{at}scripps.edu.

Molecular and Cellular Biology, October 2004, p. 8408-8417, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8408-8417.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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