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Departments of 1 Cell Biology and 3 Surgery, Yale University, New Haven, Connecticut 06520; and Departments of 2 Medicine and 4 Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599
Tight junctions (TJs) regulate
paracellular permeability across epithelia and vary widely in their
transepithelial electrical resistance (TER) and charge selectivity. The
claudin family of transmembrane proteins influences these properties.
We previously reported that claudin-4 increased TER ~300% when
expressed in low-resistance Madin-Darby canine kidney (MDCK) II cells
and decreased the paracellular permeability for Na+ more
than Cl
(Van Itallie C, Rahner C, and Anderson JM.
J Clin Invest 107: 1319-1327, 2001). In
comparison, we report here that expression of claudin-2 increases TER
by only ~20% and does not change the ionic selectivity of MDCK II
cells from their cation-selective background. To test whether the
extracellular domains of claudins-4 and -2 determine their unique
paracellular properties, we determined the effects of interchanging
these domains between claudins-4 and -2. Inducible expression of
wild-type claudins and extracellular domain chimeras increased both the
number and depth of fibrils, but the characteristic fibril morphologies
of claudin-4 or -2 were not altered by switching extracellular domains.
Like claudin-4, chimeras expressing the first or both extracellular
domains of claudin-4 on claudin-2 increased TER severalfold and
profoundly decreased the permeability of Na+ relative to
Cl. In contrast, chimeras expressing the first or both
extracellular domains of claudin-2 on claudin-4 increased the TER by
only ~60 and ~40%, respectively, and only modestly altered charge
selectivity. These results support a model in which the claudins create
paracellular channels and the first extracellular domain is sufficient
to determine both paracellular charge selectivity and TER.
tight junction; claudin-4; claudin-2; dilution potential; intercellular junction; transepithelial electrical resistance
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