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Originally published online as doi:10.2353/ajpath.2008.070698 on March 18, 2008

Published online before print March 18, 2008
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(American Journal of Pathology. 2008;172:905-915.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070698

A Key Claudin Extracellular Loop Domain is Critical for Epithelial Barrier Integrity

Randall J. Mrsny{dagger}, G. Thomas Brown*, Kirsten Gerner-Smidt*, Andre G. Buret{ddagger}, Jon B. Meddings§, Clifford Quan, Michael Koval|| and Asma Nusrat*

From the Department of Pathology,* Emory University, Atlanta, Georgia; Department of Pharmacy and Pharmacology,{dagger} University of Bath, Bath, United Kingdom; Department of Biological Sciences,{ddagger} University of Calgary, Calgary, Alberta, Canada; Department of Medicine,§ University of Alberta, Edmonton, Alberta, Canada; Bioorganic Chemistry, Genentech, Inc., South San Francisco, California; and the Department of Medicine,|| Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University, Atlanta, Georgia

Intercellular tight junctions (TJs) regulate epithelial barrier properties. Claudins are major structural constituents of TJs and belong to a large family of tetra-spanning membrane proteins that have two predicted extracellular loops (ELs). Given that claudin-1 is widely expressed in epithelia, we further defined the role of its EL domains in determining TJ function. The effects of several claudin-1 EL mimetic peptides on epithelial barrier structure and function were examined. Incubation of model human intestinal epithelial cells with a 27-amino acid peptide corresponding to a portion of the first EL domain (Cldn-153–80) reversibly interfered with epithelial barrier function by inducing the rearrangement of key TJ proteins: occludin, claudin-1, junctional adhesion molecule-A, and zonula occludens-1. Cldn-153–80 associated with both claudin-1 and occludin, suggesting both the direct interference with the ability of these proteins to assemble into functional TJs and their close interaction under physiological conditions. These effects were specific for Cldn-153–80, because peptides corresponding to other claudin-1 EL domains failed to influence TJ function. Furthermore, the oral administration of Cldn-153–80 to rats increased paracellular gastric permeability. Thus, the identification of a critical claudin-1 EL motif, Cldn-153–80, capable of regulating TJ structure and function, offers a useful adjunct to treatments that require drug delivery across an epithelial barrier.






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