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doi: 10.1242/10.1242/jcs.00165

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Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells

¹ Department of Clinical Physiology, Benjamin Franklin Medical School, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany
² Department of Gastroenterology, Infectiology and Rheumatology, Benjamin Franklin Medical School, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany
³ Department of Pharmacology, Benjamin Franklin Medical School, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany

^* Author for correspondence (e-mail: michael.fromm{at}medizin.fu-berlin.de)

Accepted 11 September 2002

Tight junctions seal the paracellular pathway of epithelia but, in leaky tissues, also exhibit specific permeability. In order to characterize the contribution of claudin-2 to barrier and permeability properties of the tight junction in detail, we studied two strains of Madin-Darby canine kidney cells (MDCK-C7 and MDCK-C11) with different tight junctional permeabilities.

Monolayers of C7 cells exhibited a high transepithelial resistance (>1 k cm²), compared with C11 cells (<100 cm²). Genuine expression of claudin-1 and claudin-2, but not of occludin or claudin-3, was reciprocal to transepithelial resistance. However, confocal microscopy revealed a marked subjunctional localization of claudin-1 in C11 cells, indicating that claudin-1 is not functionally related to the low tight junctional resistance of C11 cells.

Strain MDCK-C7, which endogenously does not express junctional claudin-2, was transfected with claudin-2 cDNA. In transfected cells, but not in vector controls, the protein was detected in colocalization with junctional occludin by means of immunohistochemical analyses. Overexpression of claudin-2 in the originally tight epithelium with claudin-2 cDNA resulted in a 5.6-fold higher paracellular conductivity and relative ion permeabilities of Na⁺1, K⁺=1.02, NMDG⁺=0.79, choline⁺=0.71, Cl^-=0.12, Br^-=0.10 (vector control, 1:1.04:0.95:0.94:0.85:0.83). By contrast, fluxes of (radioactively labeled) mannitol and lactulose and (fluorescence labeled) 4 kDa dextran were not changed. Hence, with regular Ringer's, Na⁺ conductivity was 0.2 mS cm^-2 in vector controls and 1.7 mS cm^-2 in claudin-2-transfected cells, while Cl^- conductivity was 0.2 mS cm^-2 in both cells. Thus, presence of junctional claudin-2 causes the formation of cation-selective channels sufficient to transform a `tight' tight junction into a leaky one.

Key words: Zonula occludens, Claudins, Occludin, Transepithelial resistance, Impedance analysis

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