Claudins: vital partners in transcellular and paracellular transport coupling

Tight junction (TJ) strands between epithelial or endothelial cells are formed by claudins, a protein family comprising up to 27 members in mammals. Although many more proteins are involved in the formation of TJ complexes, claudins are the only TJ proteins that are able to form TJ-like strands when overexpressed in cells that are normally devoid of TJs (e.g., fibroblasts). Within the paracellular cleft, the extracellular domains of claudins provide the matrix that seals the paracellular pathway. However, within this matrix, some claudins act as channels that specifically allow certain ions to cross this barrier. Barrier-forming claudins predominate in epithelia that enclose compartments containing harmful ion concentrations (e.g., H⁺ in the stomach, K⁺ in the inner ear endolymph) or high pressures (e.g., in blastocoel or brain ventricle formation during development). Here, even seemingly minor alterations in TJ composition may be detrimental to the organism. In contrast, in many transporting epithelia, channel-forming claudins are essential for transcellular and paracellular transport coupling. Mutation or knockout of channel-forming claudins in these tissues brings both transcellular and paracellular transports to a standstill. The present review will present examples to illustrate the importance of single members of the claudin family in general epithelial transport physiology.