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5 and 6

These isoenzymes can be separated by agar gel electrophoresis at pH 5.0 or anion exchange high-performance liquid chromatography.

These isoenzymes can be separated by agar gel electrophoresis at pH 5.0 or anion exchange high-performance liquid chromatography.

14 500 molecular weight protein and proteoglycan. Also, unlike the other pepsins, pepsin 1 is secreted only in the fundic and not the pyloric glands and is only present in significant amounts in stimulated juice. Pepsin 1 has the highest molecular weight (44 500), while the other pepsins have molecular weights around 35 000. The pH optimum against protein substrates for all pepsins is in the acidic range 1.9-3.6. Pepsin 1 secretion is elevated in peptic ulcer disease (PUD) and is therefore the pepsin associated with ulcers. Also associated with peptic ulcer disease is the bacteria Helicobacter pylori (HP), which colonizes the stomach at the epithelia surface under the mucous layer. Helico-bacter pylori is believed to protect itself from the acid environment of the stomach by the action of a membrane-bound urease, which generates ammonia from the urea present in gastric juice. Interestingly, approximately 50% of all people in the UK over 50 years old are HP positive, yet only a small proportion of these will develop peptic ulcer disease. The increased secretion of pepsin 1 in PUD may be explained by HP infection.

Pepsinogen secretion The initial stimulus for pepsi-nogen comes from feeding. There is a basal level of secretion, which is 20% of the stimulated secretion. Maximal secretion produces gastric juice with a pepsin concentration approaching 1mgml-1. There is a biphasic response with initial release of stored pepsinogen in a rapid phase (20-40 min) followed by a less rapid steady state of secretion. Pepsinogen secretion is stimulated by CCK, forskolin, and by insulin induced hypoglycemia mediated by the vagus nerve. Gastrin also stimulates pepsinogen secretion; however, it is much less effective than CCK. Secretion is also stimulated by the peptide hormones secretin and vasoactive intestinal peptide (VIP) and by adrenaline acting through receptors and by prostaglandins and histamine. All these agents alter intracellular cAMP levels, which in turn activates cAMP-dependent protein kinase (PKA) associated with A-kinase anchoring protein-150 (AKAP-150). Pepsinogen secretion is stimulated by cholinergic agents acting on muscarinic M3 subtype receptors; these agents also stimulate acid secretion. Acetylcho-line and the CCK/gastrin family act through altering intracellular Ca2+ and Inositol triphosphate (IP3) levels. The elevation of intracellular calcium is produced by release from intracellular stores and an influx of calcium via a membrane cation channel. Helicobacter pylori is believed to increase pepsino-gen secretion via this Ca2+ signal transduction pathway. Recently, the G protein-coupled protease activated receptor-2 (activated by partial digestion)

on chief cells has been shown to stimulate pepsino-gen secretion when activated. Pepsinogen is secreted by compound exocytosis with granules fusing together and with the plasma membrane. The enzyme is condensed within the vesicle in association with a divalent cation, e.g., Ca2+. Initial fusing with the plasma membrane produces a small pore releasing the Ca2+, causing the vesicle contents to swell producing a larger pore through which the pepsinogen is released.

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