Claudin-2-dependent changes in noncharged solute flux are mediated by the extracellular domains and require attachment to the PDZ-scaffold.

Paracellular transport through the tight junction shows selectivity for both ionic charge and solute size. It is known that charged residues on the extracellular loops of claudins control charge selectivity. It is also known that inducible expression of claudin-2, but not claudin-4, will selectively increase the permeability for polyethylene glycol (PEG) molecules which are <0.4 A in radius, but it is not known whether permeability is controlled by the same regions of claudins which control charge selectivity. Using inducible expression of chimeras of claudin-2 and claudin-4 in monolayers of MDCK II cells we show that the extracellular loops alone are responsible for controlling the permeability for noncharged PEGs as well as for charge selectivity. Further, the cytoplasmic C-terminal PDZ-binding motif is required for wild-type claudin-2 to control permeability, suggesting a requirement for attachment to the PDZ scaffold in order to form pores. These observations support a model where the loops form pores controlling permeability for both charged and noncharged solutes which are smaller than 0.4 A. They leave unanswered why both claudin-2 and -4 can influence electrical properties while only -2 can selectively increase permeability for small PEGs.