The Journal of General Physiology
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Published online December 29, 2008
doi:10.1085/jgp.200810154
The Journal of General Physiology, Vol. 133, No. 1, 111-127
The Rockefeller University Press, 0022-1295 $30.00
© 2008 Yu et al.
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ARTICLE

 Molecular Basis for Cation Selectivity in Claudin-2–based Paracellular Pores: Identification of an Electrostatic Interaction Site



Alan S.L. Yu1,2, Mary H. Cheng3, Susanne Angelow1, Dorothee Günzel4, Sanae A. Kanzawa1, Eveline E. Schneeberger5, Michael Fromm4, and Rob D. Coalson3

1 Division of Nephrology, Department of Medicine, and 2 Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, CA 90089
3 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260
4 Institute of Clinical Physiology, Charité, Campus Benjamin Franklin, 12200 Berlin, Germany
5 Department of Pathology, Massachusetts General Hospital, Boston, MA 02114

Correspondence to Alan S.L. Yu: alanyu{at}usc.edu

Paracellular ion transport in epithelia is mediated by pores formed by members of the claudin family. The degree of selectivity and the molecular mechanism of ion permeation through claudin pores are poorly understood. By expressing a high-conductance claudin isoform, claudin-2, in high-resistance Madin-Darby canine kidney cells under the control of an inducible promoter, we were able to quantitate claudin pore permeability. Claudin-2 pores were found to be narrow, fluid filled, and cation selective. Charge selectivity was mediated by the electrostatic interaction of partially dehydrated permeating cations with a negatively charged site within the pore that is formed by the side chain carboxyl group of aspartate-65. Thus, paracellular pores use intrapore electrostatic binding sites to achieve a high conductance with a high degree of charge selectivity.

Abbreviations used in this paper: DMC, dynamic Monte Carlo; MDCK, Madin-Darby canine kidney; TM, triple mutant; WT, wild-type.

© 2009 Yu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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A. S.L. Yu, M. H. Cheng, S. Angelow, D. Gunzel, S. A. Kanzawa, E. E. Schneeberger, M. Fromm, and R. D. Coalson
Molecular Basis for Cation Selectivity in Claudin-2-based Paracellular Pores: Identification of an Electrostatic Interaction Site
J. Cell Biol., January 12, 2009; 184(1): i3 - i3.
[Full Text]


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