Physiology and function of the tight junction

Abstract

Understanding of tight junctions has evolved from their historical perception as inert solute barriers to recognition of their physiological and biochemical complexity. Many proteins are specifically localized to tight junctions, including cytoplasmic actin-binding proteins and adhesive transmembrane proteins. Among the latter are claudins, which are critical barrier proteins. Current information suggests that the paracellular barrier is most usefully modeled as having two physiologic components: a system of charge-selective small pores, 4 A in radius, and a second pathway created by larger discontinuities in the barrier, lacking charge or size discrimination. The first pathway is influenced by claudin expression patterns and the second is likely controlled by different proteins and signals. Recent information on claudin function and disease-causing mutations have led to a more complete understanding of their role in barrier formation, but progress is impeded by lack of high resolution structural information.

Figure 1.

Electrical circuit model of the series and paracellular resistances across trans- and paracellular pathways of an epithelial cell monolayer. Transcellular transport is controlled by transporters in the apical and basolateral surfaces. The resistance of these series elements is typically much higher than that of the parallel elements of the paracellular pathway. Thus, the overall resistance of an epithelium is defined by R_TJ, which is defined by the composition of claudins in the tight junction (TJ).

Figure 2.

(A) The first extracellular loops of several claudins, which have been tested for charge selectivity. Residue numbering is based on the sequence of claudin-2. Numerous shaded positions alter selectivity when mutated. Alternatively, the boxed residues around residue 65 have been suggested to be the most critical in determining selectivity. Signature W-GLW-C-C residues are underlined. (B) Conceptual model of the claudin-based TJ barrier. The first extracellular loop contains the electrostatic selectivity filter of the pore and the second loop the cell–cell adhesion sites. In an unknown way, claudin monomers assemble into continuous strands within each cell membrane and adhere across the intercellular space to create a barrier with size and charge-selective pores.

Figure 3.

The two pathway model. Idealized data show the permeability of noncharged polyethylene glycol molecules of different sizes across an epithelium. The pathway for molecules below 4 Å is formed by claudin pores that are size and charge selective. The pathway for molecule above 4 Å in diameter shows no charge selectivity and appears to be defined by the status of cell-to-cell adhesion and the cytoskeleton.