Epithelial cells are networked together through proteinaeous adhesive contacts called junctions, wich both join cells together and provide a paracellular seal. The seal between cells requires tight junctions (TJs), a specialized multipurpose adhesion that simultaneously occludes the paracellular space, dictates ion flux across the tissue, and maintains cellular polarity. The Tjs are positioned at the boundary of the apical and lateral membrane surfaces of adjacent epithelial cells in the colon and consist of 5-7 membrane fusion sites called kissing points. The entire circumference of each cell is joined to apposing cells via an adhesive TJ band, called a strand. TJs strands in the colon are no linear but rather highly branched structures that form anastomosed webs that extend several hundred nanometers laterally from the apex of the cell.All epithelial cells that line the intestine are joined in this manner.
The epithelial tight junction proteins, the most apical component of epithelial intracelular junctions, seals the paracellular space between the cells and tightly restricts the transport of hydrophilic molecules (gate and fence function). Any alteration in the TJ structure can prove to be detrimental to the organism
The uptake of lipophilic or large molecules through the intestinal barrier is highly restricted. The uptake of lipophilic or large molecules is mostly dependent on diffusion and endocytosis. The three most important complexes are: Tjs, adherens junctions (AJs) and desmosomes. Tjs are the apical-most adhesive complexes that largely seal the intercellular space,and consist of transmembrane proteins (e.g. claudins,occludin), peripheral membrane proteins (e.g. zonula occludens (ZO)-1, ZO-2) and regulatory proteins.
From apical-to-basal, the intercellular junctions are: the tight junction (zonula occludens),the adherens junction (zonula adherens), and the desmosome. Together these three types of intercellular junctions comprise the apical junctional complex (AJC). The AJC is associated with a dense network of actin and myosin that encircles the apical aspect of each cell and surrounds the cortical actin web.The latter supports the dense microvillus brush border,while, the perijunctional actomyosin ring regulates epithelial barrier function.
Adherens junctions and desmosomes provide adhesive forces necessary for maintenance of cell-cell interactions. The most well-known component of the adherens junctions are the cadherins, single spanning transmembrane proteins that interact homotypically with the extracellular portion of cadherins on adjacent cells.
The TJ is the primary determinant of paracellular permeability.When viewed by transmission electron microscopy, the TJ appears to eliminate the intracellular space at so-called kissing points, and freeze-fracture electron microscopy clearly depicts the TJs consist of a series of anastomosing strands.
Tight junction proteins
- Transmembrane proteins: the tetraspanning claudins are the most important, the extracellular domains of claudins on adjacent cells form pores to regulate TJ ion selectivity.
- Cytosolic plaque or scaffolding proteins: The ZO family proteins (ZO-1,-2,-3) are multi-domain scaffolding proteins that interact directly with transmembrane TJ proteins (claudins) and the TJ associated Marvel protein (TAMO) family, which includes occludin. Zo family proteins also interact with the actin cytoskeleton and a variety of actin regulatory elements.
Paracellular permeability pathways
The TJ barrier exhibits both size- and charge-selectivity. There are two distinct routes across TJs of an intact epithelial monolayer, termed the pore and leak pathways. The pore pathway refers to a high-capacity,site- and charge-selective route,whereas the leak pathway is a low-capacity pathway that has limited selectivity.
Pore pathway appears to be determined primarily by the subset of claudins expressed, whereas the leak pathway is a low-capacity pathway that has limited selectivity. Pore pathway permeability appears to be determined primarily by the subset of claudins expressed,while leak pathway permeability can be regulated by ZO-1, occludin,myosin light chain kinase (MLCK).
At sites of epithelial damage, TJs are lost and, by definition,cannot contribute to local barrier function. Luminal contents cross the intestinal barrier by a third pathway (unrestricted pathway).