1

R Minimal fragment for strong activity

FIGURE 5 Structure of human ''little'' gastrin (HG-17).

originally isolated from hog antral mucosa as a hepta-decapeptide called G-17 or "little" gastrin. The form shown in Fig. 5 is human G-17 and differs from the gastrins of other species only by one or two amino acid substitutions in the middle of the molecule. Little gastrin accounts for about 90% of the gastrin found in antral mucosa. The major component of gastrin in serum of fasting subjects, however, is a larger molecule called "big" gastrin. On isolation, big gastrin was found to contain 34 amino acids, and is therefore called G-34. Trypsin splits G-34 to yield G-17 plus another inactive heptadecapeptide. Therefore, G-34 is not a dimer of G-17. Current evidence indicates that G-17 is not produced from G-34 or vice versa, because both pro G-17 and pro G-34 are produced. Between meals, referred to as the interdigestive state, most human serum gastrin is G-34. The human duodenal mucosa also contains significant amounts of gastrin, which is predominantly G-34. In response to a meal, a large amount of antral G-17 is released along with smaller amounts of G-34 from the antral mucosa. G-34 may be released from duodenal mucosa under special conditions. G-17 and G-34 are equipotent, although the half-life of G-34 is 38 min and the half-life of G-17 is approximately 7 min.

Radioimmunoassay of plasma from normal fasting humans gives values between 50 and 100 pg/mL (pg or picogram= 10—12 g). During a meal, these values usually increase 50-100%.

In Fig. 5, note that position 12 is a tyrosyl residue. If the tyrosine is sulfated, the molecule is called gastrin II; unsulfated, it is called gastrin I. Both forms occur with equal frequency in nature and are equipotent for most effects. The N terminus of gastrin is a pyroglutamyl residue (Glp). The -NH2 group that follows the C-terminal Phe indicates that this is the amidated form, phenylalamide. The pyroglutamyl and phenylala-mide residues protect gastrin from amino peptidases and carboxypeptidases.

The most interesting structural feature of gastrin is that all the biologic activity is contained in the four

C-terminal amino acids. This tetrapeptide is the minimal fragment of gastrin necessary for strong activity and is about one-sixth as potent as the whole hormone.

The physiologically significant actions of gastrin are the stimulation of gastric acid secretion and its trophic activity (Table 1). The receptor for gastrin in the so-called CCK-B or CCK-2 receptor, which also binds CCK, but its affinity for CCK is much lower than its affinity for gastrin. Gastrin stimulates acid secretion by acting directly on the acid-secreting parietal cell and by releasing histamine from the enterochromaffin-like cell (ECL cell). Gastrin also stimulates histamine synthesis in, and growth of, the ECL cells. On a molar basis, gastrin is 1500 times more potent than histamine for stimulating acid secretion. Gastrin stimulates the growth of the oxyntic gland (acid-secreting portion) mucosa of the stomach and also the colonic mucosa. If most endogenous gastrin is surgically removed by resecting the gastric antrum, these tissues atrophy. Patients having high serum levels of gastrin because of continual release of the hormone from a tumor have hyperplasia and hypertrophy of the acid-secreting portion of the stomach. The trophic actions of gastrin and the other GI hormones are direct effects and are specific for GI tissues. There is considerable interest in the role of gastrin in promoting the growth of colon cancers. Many colon tumors have receptors for gastrin and some also secrete the hormone, which may act as an autocrine agent. Interestingly, progastrin and glycine extended G-17 and G-34, steps in the synthesis of the hormone, are sometimes secreted and have trophic effects.

Gastrin is physiologically released from G cells of the antral mucosa, and to a lesser extent the duodenal mucosa, in response to a meal. The most important releasers are protein digestion products, small peptides, and amino acids (Table 1). Phenylalanine and trypto-phan are the amino acids with the greatest gastrin-releasing activity. The release of gastrin requires luminal contact with the antral mucosa because intravenous amino acids are ineffective. Activation of the vagus and local cholinergic reflexes also release gastrin. The vagal mediator of gastrin release is bombesin (also called gastrin-releasing peptide, GRP). Gastrin is also released by physical distension of the wall of the stomach. For example, inflating a balloon in the antrum initiates a reflex release of gastrin. This response is triggered during a meal by the pressure of ingested food.

Release of gastrin is inhibited by acidification of gastric luminal contents below pH 3. This is an important feedback inhibition of gastrin release and ensures that additional gastrin is not released when the stomach is already acidified. It is important to realize that raising the pH by neutralizing gastric contents does

Get Rid of Gallstones Naturally

Get Rid of Gallstones Naturally

One of the main home remedies that you need to follow to prevent gallstones is a healthy lifestyle. You need to maintain a healthy body weight to prevent gallstones. The following are the best home remedies that will help you to treat and prevent gallstones.

Get My Free Ebook


Post a comment