Mucus

The mucus covering the surface of the stomach consists of a mixture of many secretions and exfoliated cells. The major viscous and gel-forming component of the mucus gel is mucin, present at approximately 40mgml-1 in the firm layer and approximately 15mgml-1 in the sloppy layer. Mucin is also present in gastric juice resulting from pepsin erosion of the surface of the gel. It is secreted by the surface epithelial cells and mucous neck cells and is a glycoprotein, about 80% carbohydrate. The core protein of mucin has large regions of amino acid tandem repeats, variable in number (VNTR), which are different for different mucins. The VNTR regions are the sites of heavy glycosylation. The N- and C-terminal regions of the protein core are globular and rich in cysteine and contain domains like those in von-Willebrand factor, a glycoprotein involved in blood clotting, which polymerizes via disulfide bridges. Mucin units are therefore polymerized via disulfide bridges into polymers with molecular weights of about 10 x 106 (Figure 7).

Polymerization is essential for gel formation, which results from noncovalent interactions between polymers. Also present in the gel and the gastric juice, secreted by mucin secretory cells are IgA, which combats bacterial invasion and trefoil peptides (mol. wt. 5000-10 000), which may interact with mucin to stabilize and strengthen the

Mucin polymer: gel forming, insoluble

Globular D domains

Globular D domains

Densely glycosylated regions (VNTR)

Densely glycosylated regions (VNTR)

Disulfide bridges linking subunits into polymers

Protein core

Protein core

Proteolysis by pepsin in sparsely glycosylated regions of the protein core

Mucin glycoprotein: proteinase _|||||||||||||||||||_ resistant, soluble lllllllllllllllllll

Figure 7 Model for the structure of gastric mucin. Mucin genes expressed in the stomach are MUC5AC and MUC6, both of which are encoded for on chromosome 11 on the p arm at position 15.5. Both MUC5AC and MUC6 have cysteine-rich globular domains on the C- and N-terminals of the mucin units, thus allowing end-to-end polymerization via disulfide bridges. The mucin D domains are homologous to the D domains present in the clotting factor von Willebrand factor, suggesting a common ancestor. MUC5AC has four D domains on its N-terminal and one D domain and a cysteine-rich structure called a cysteine knot on its C-terminal. MUC6 has the same N-terminal structure but only has the cysteine knot on its C-terminal. *Regions susceptible to proteolysis.

gel. IgA inhibit acid secretion and gastric motility, however their major function is as a growth factors, a promoters of gastric healing, and suppressors of tumor growth.

Mucin secretion Mucin secretion is by compound exocytosis and may be linked to Cl- secretion, with the mucin polyanion stored inside granules condensed with Ca2+-mediated charge shielding. The exocytosis mechanism is similar to that for pepsino-gen. There are two routes: (1) constitutive, with a steady release from the cells; and (2) regulated, with release from storage granules. Muscarinic receptors mediate mucin secretion. Cholinergic agonists stimulate secretion via protein kinase C and IP3 leading to an increase in intracellular Ca2+. ^-adrenergic agents, secretin and prostaglandins E2 and F2/3 stimulate secretion via a cAMP-mediated mechanism and NO acts via cGMP. Inflammation and infection, mediated by the cytokines TNFa, Il-6, and Il-8 and bacterial cell wall components (e.g., lipopolysac-charides), as well as epithelial damaging agents (e.g., free radicals and mustard oil) stimulate mucin secretion.

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