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Participation of the second extracellular loop of claudin-5 in paracellular tightening against ions, small and large molecules
Authors:Christian Piehl  Jörg Piontek  Jimmi Cording  Hartwig Wolburg  Ingolf E Blasig
Institution:1. Leibniz-Institut für Molekulare Pharmakologie, FMP, Robert-R?ssle-Str. 10, 13125, Berlin, Germany
2. Institute of Pathology, University of Tübingen, Liebermeisterstra?e 8, 72076, Tübingen, Germany
Abstract:Tight junctions control paracellular permeability. Here, we analyzed the impact of residues in the second extracellular loop (ECL2) of mouse claudin-5 on paracellular permeability. Stable expression of claudin-5wild type in MDCK-II cells—but not that of mutants R145A, Y148A, Y158A or E159Q—increased transepithelial electrical resistance and decreased fluorescein permeation. Expression of claudin-5Y148A, Y158A or E159Q enhanced permeability of FITC-dextran10 kDa, which was unchanged in cells expressing claudin-5wild type or claudin-5R145A. In contrast, targeting to tight junctions, strand morphology and tight junction assembly were unchanged. It is concluded that R145 is unessential for trans-interaction of claudin-5, but necessary for tightening against small solutes and ions. The highly conserved residues Y148, Y158 and E159 in ECL2 of claudin-5 contribute to homo- and/or heterophilic trans-interaction between classic claudins and thereby tighten the paracellular space against ions, small and large molecules. These results provide novel insights into the molecular function of tight junctions.
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