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Tight junctions are molecular seals between cells that prevent the leaking of fluids, ions, and other small solutes across cavities and compartments in multicellular organisms. They are mainly composed of claudin and occludin transmembrane proteins, and other proteins such as tricellulin and JAM (junctional adhesion molecule). All these proteins are 4-pass transmembrane proteins, except JAM, which is a single-pass transmembrane protein belonging to the immunoglobulin superfamily. The extracellular domains of these tight junction proteins interact with those on the adjacent cell membrane, thus bringing together and sealing the two adjacent cells.

Selective Permeability of Tight Junctions

There are multiple isoforms of the transmembrane claudin, with up to 24 different types expressed in humans. The diversity of the claudin protein confers selective permeability to different tight junctions. For example, claudin-16, expressed in the kidney epithelium increases permeability to magnesium ions, thereby allowing their reuptake from the blood during filtration. In contrast, the claudin-5 expressed in the endothelial cells of the brain capillaries selectively decreases ion permeability across the blood-brain barrier.

Tricellular Junctions

In addition to sealing gaps between two cells, tight junctions also seal the gaps formed at the junction of three cells - a tricellular junction. The structure of tricellular junctions was first observed in the 1970s using freeze-fracture electron microscopy. At these junctions, the sealing strands are oriented perpendicularly to the strands of the bicellular tight junctions. The tricellular contact point thus forms a narrow vertical tube about 10nm diameter, that controls the paracellular movement of molecules.

Tricellulin was the first protein identified to concentrate at these tricellular junctions. It shares sequence homology with the occludin proteins and exhibits four isoforms in humans. Interestingly, mutations in the tricellulin gene, TRIC, are shown to cause hearing impairment, demonstrating its importance in maintaining tight seals such as those required in the organ of Corti - a structure in the inner ear.

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