Non-canonical functions of claudin proteins: Beyond the regulation of cell-cell adhesions

Tight junctions form a barrier to the diffusion of apical and basolateral membrane proteins thus regulating membrane polarity. They also regulate the paracellular movement of ions and water across epithelial and endothelial cells so that functionally they constitute an important permselective barrier. Permselectivity at tight junctions is regulated by claudins, which confer anion or cation permeability, and tightness or leakiness, by forming several highly regulated pores within the apical tight junction complex. One interesting feature of claudins is that they are, more often than not, localized to the basolateral membrane, in intracellular cytoplasmic vesicles, or in the nucleus rather than to the apical tight junction complex. These intracellular pools of claudin molecules likely serve important functions in the epithelium. This review will address the widespread prevalence of claudins that are not associated with the apical tight junction complex and discuss the important and emerging non-traditional functions of these molecules in health and disease.