A crucial function of the intestinal epithelial cells is the maintenance of barrier integrity, which allows the permeability of essential ions,nutrients,and water but restricts the entry of bacterial toxins and pathogens. The transport of molecules across the epithelial layer ours through three major pathways: the trans-cellular pathway (passive diffusion across the cell membranes), the carrier-mediated pathway (carrier/receptor-mediated transcellular pathway),and the paracellular pathway (passive diffusion between the sapes through adjacent cells). The epithelial tight junction proteins, the most apical component of epithelial intracellular junctions seals the paracellular space between the cells and tightly restricts the transport of hydrophilic molecules. Claudins, one of the major tight junction proteins, are responsible for the regulation of paracellular space.Claudins are cell-cell adhesions molecules localized in the tight junction (TJs) between cells in epithelial cells sheets. The claudin family in mammals consist of 27 four-transmembrane domain proteins. The are several isoforms of claudin, each having potentially different roles, and a fine balance between them is needed for the maintenance of paracellular integrity. Claudins are expressed in both endothelial and epithelial cells.
The main function attributed to the tight junction proteins is the gate and fence function, which allows the paracellular transport of some solutes and molecules but prevents the intramembrane transport of proteins,lipids, and microbial-derived peptides.
There are several isoforms of claudin, each having potentially different roles, and a fine balance between them is needed for the maintenance of paracellular integrity. Alterations in the claudin levels can affect the intestinal barrier integrity in different ways depending on the type of claudin isoform. Claudins have been proposed to function as tight or sealing claudins or as leaky pore-forming claudins. The paracellular pore properties have been attributed to claudin amino acid composition in the first extracellular loop (EC1). Pore- or channel-forming claudins have selectivity for charged ions and water. Cysteine residues in the EC1 enhance the stability of the protein, while the smaller second extracellular loop (EC2) mediate claudin-claudin interactions within the cell (cis) and in adjoining cells (trans).The majority of claudins, with a few exceptions, such as claudin-23, contain a PDZ (PSD95,D1g1,and ZO-1) binding motif that associates with submembrane plaque proteins containing PDZ domains and regulatory molecules, which serve to organize and control TJ structure and ultimately epithelial barrier function.The most extensively studied cytoplasmic plaque PDZ domain-containing proteins are the zonula ocludens (ZO)proteins, which includes ZO-1 and ZO-2.Freeze-fracture ultrastructural analysis has revealed that claudins reside and organize TJ strands between cells.
Such TJ protein-actin cytoskeleton affiliations control physiologic epithelial barrier properties and are targeted in pathologic states associated with barrier compromise
Schematic functional domains and key binding partners that mediate intestinal epithelial homeostasis.
The composition of epithelial claudins not only varies spatially along the length of the gastrointestinal tract but also in the crypt-luminal axis as epithelial cells transition from proliferative to differentiated phenotype.It is remarkable that such claudin remodeling occurs within a few days during the life span of the intestinal epithelium that maintains and yet modifies its barrier properties. A number of studies have investigated the spatiotemporal distribution of claudins proteins in the intestine.
In addition to their pivotal role in controlling barrier function, claudins regulate epithelial homeostasis that encompasses proliferation and differentiation of cells. Dysregulation of claudins proteins has been observed in inflammatory states associated with a leaky epithelial barrier, as well as in neoplastic states
Depending on the stimulus, select junctional proteins, including claudins, are internalized from the cell surface through a number of mechanism that differentially involve clathrin, caveolin, and micropinocytosis pathways. Claudin family members exhibit differential dynamics within TJs.
Spatiotemporal expression of claudin proteins
The specific organization of claudins in adult differs from that in the developing intestine. At the cellular level claudin proteins can be either targeted exclusively to the TJ or also reside in the lateral membrane of polarized epithelial cells. Lateral expression of claudin-7 has been proposed to have signaling properties that influence maintenance of extracellular matrix interactions,homeostasis,and differentiation.