Tight junction pores

Van Itallie CM and Anderson JM [2004] The Molecular Physiology of Tight Junction Pores. Physiology 19 331-338... 

Van Itallie, C.M., and J.M. Anderson. 2004. The molecular physiology of tight junction pores. 

The in vitro system we have been using to study the transepithelial transport is cultured Madin-Darby canine kidney (MDCK) epithelial cells (11). When cultured on microporous polycarbonate filters (Transwell, Costar, Cambridge, MA), MDCK cells will develop into monolayers mimicking the mucosal epithelium (11). When these cells reach confluence, tight junctions will be established between the cells, and free diffusion of solutes across the cell monolayer will be markedly inhibited. Tight junction formation can be monitored by measuring the transepithelial electrical resistance (TEER) across the cell monolayers. In Figure 1, MDCK cells were seeded at 2 X 104 cells per well in Transwells (0.4 p pore size) as described previously. TEER and 14C-sucrose transport were measured daily. To determine 14C-sucrose... 

The membrane surface facing the lumen is called the apical surface, and the membrane surface on the side facing blood is called the basolateral surface. The intestinal cells are joined at the tight junctions [63,75]. These junctions have pores that can allow small molecules (MW < 200 Da) to diffuse through in aqueous solution. In the jejunum, the pores are 7-9 A in size. In the ileum the junctions are tighter, and pores are 3-4 A in size (i.e., dimensions of mannitol) [63]. 

Many structural components of the tight junctions (TJs) have been defined since 1992 [85-97]. Lutz and Siahaan [95] reviewed the protein structural components of the TJ. Figure 2.7 depicts the occludin protein complex that makes the water pores so restrictive. Freeze-fracture electronmicrographs of the constrictive region of the TJ show net-like arrays of strands (made partly of the cytoskeleton) circumscribing the cell, forming a division between the apical and the basolateral... 

The paths of the tight junctions and lateral spaces are assumed to be cylindrical pores and slits, respectively. The Renkin function F(r/R), for the tight junction is defined by Eq. (35), but the function G(r/R ) for the lateral space (Curry, 1984) is... 

The oral administration of large proteins and peptides is limited due to their low membrane permeability. These compounds are mainly restricted to the para-cellular pathway, but because of their polar characteristics and their size the pore of the tight junctional system is also highly restrictive. An additional transcellular pathway has therefore been suggested for these peptides, i.e., the transcytotic pathway, which involves a receptor-mediated endocytosis in Caco-2 cells [126],... 

There are two pathways by which a drug molecule can cross the epithelial cell the transcellular pathway, which requires the drug to permeate the cell membranes, and the paracellular pathway, in which diffusion occurs through water-filled pores of the tight junctions between the cells. Both the passive and the active transport processes may contribute to the permeability of drugs via the transcellular pathway. These transport pathways are distinctly different, and the molecular properties that influence drug transport by these routes are also different (Fig. 

Tight junction elements are modeled as pores that flicker between open and closed states [131], such that each small segment can be at one of two states, sealed (rciosed) or open (ropen) (r being referred to as the microscopic... 

Tsukita S and Furuse M [2000] Pores in the wall claudins constitute tight junction strands containing aqueous pores. J Cell Biol 149 13-16... 

Saitoh, R., Sugano, K., Takata, N., Tachibana, T., Higashida, A., Nabuchi, Y., and Aso, Y., Correction of permeability with pore radius of tight junctions in Caco-2 monolayers improves the prediction of the dose fraction of hydrophilic drugs absorbed by humans, Pharm. Res., 21, 749, 2004. 

Usually, PAMPA does not have any aqueous pores and is therefore not suitable for examining paracellular transport. Some cell models, for example, Caco-2 and MDCK, have a narrower tight junction than the in vivo human intestine and may underestimate paracellular transport. However, the contribution of the paracellular pathway can be added using an in silico approach [76-78]. 

Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space, cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000-30,000. See Figure 1-5A. 

There are tight junctions between the endothelial cells in the capillaries leaving few, if any, pores. 

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