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Peptide and Protein Hormones ------6. Cholecystokinin and Gastrin

Author:N/A    | Post time:2012-05-26

6. Cholecystokinin and Gastrin
Top of page
1. Introduction
2. Gonadoliberin, Thyroliberin, Gonadotropins, Thyrotropin, Inhibin, and Related Hormones
3. Parathyroid Hormone and the Calcitonin Family
4. Corticoliberin – Proopiomelanocortin Cascade
5. Blood Pressure Regulating Peptides
6. Cholecystokinin and Gastrin
7. Secretin Family
8. Neurotensin [1971]
9. Motilin [2005]
10. Pancreatic Spasmolytic Peptide
Cholecystokinin (CCK), which stimulates contraction of the gallbladder, is identical to pancreozymin, which was made responsible for enzyme release from the pancreas. The counterparts of CCK in amphibians are cerulein (CRL) and related peptides, their common C-terminal pentapeptide is identical to that of gastrin.

Gastrin stimulates the release of gastric acid and pepsin in the stomach. Its activity spectrum is dictated mainly by its C-terminal pentapeptide, whereas that of CCK and CRL depends on the C-terminal heptapeptide, which should contain a sulfated tyrosine residue.

Release of CCK and GT are initiated by special peptides. A trypsin inhibitor with a structure similar to that of the epidermal growth factor has been characterized as the CCK-releasing peptide. The gastrin-releasing peptide is structurally related to bombesin from amphibians.

  6.1. Trypsin-Sensitive Cholecystokinin Releasing Peptide
A peptide with 61 amino acids has been isolated from the pancreatic juice of rats and stimulates pancreatic enzyme secretion by inducing the release of CCK. This cholecystokinin releasing peptide (CCKRP) is released in response to a diet rich in protein [1252]. It is structurally similar to the pancreatic trypsin inhibitors of the Kazal type and is classified as such [1252]. Structural similarities are found between CCKRP and the epidermal growth factor (EGF) [1253]. CCKRP also binds to EGF receptors and exerts a growthpromoting effect [1253].

  6.2. Cholecystokinin and Cerulein
  Occurrence. Cholecystokinin (CKK) [9011-97-6] is formed as prepro-CCK. The structures of h- [1254], p- [1255], and r-prepro-CCK [1256] have been elucidated via their cDNA.

CCK has been isolated in the form of peptides containing 58 (CCK-58) [1257], 39 (CKK-39), 33 (CCK-33), 22(CCK-22) [1258], 12 (CCK-12), 8 (CCK-8) [1258], 5 (CCK-5) [1259], and 4 (CCK-4 and GT-4) C-terminal amino acids. These peptides are synthesized in the brain, small intestine, and the pancreas.

The r-prepro-(24 – 32)nonapeptide (V-9-M) is found in the rat brain. It has a persisting memory-improving effect when injected into the lateral ventricle [1260].

CRL has a similar sequence to CCK-8 and has been isolated from the Australian frog, Litoria caerulea. The prepro-CRL from the skin of Xenopus laevis codes for five heterogeneous pro-CRL peptides [1261].  


  Release. Ingestion of unsaturated fats and fatty acids causes a greater release of CCK than ingestion of the corresponding saturated compounds. CCK is also released in response to the acidification of the duodenum [1262], trypsinsensitive cholecystokinin releasing peptide, bombesin [1263], depolarizing K+ concentrations, and veratridin (a Na+ channel activator) [1264].

Bile acids [1265], somatostatin, and atropine [1266] inhibit the release of CCK. Stress modulates the CCK content in the rat hypothalamus [1267].

The postprandial level of CCK in the plasma of patients with pancreatic insufficiency is lower than that of healthy persons [1268]. The plasma CCK level in patients with non-insulin-dependent diabetes [1269], hepatic cirrhosis [1270], and chronic pancreatitis [1271] is elevated.

Receptors [1272]. There are two main types of CCK receptor: CCK-A and CCK-B [1261]. The CCK-A receptors are found on pancreatic acinar cells, in the gallbladder, on adenohypophysis cells, and on inhibitory neurons of the lower esophageal sphincter. Only sulfated CCK derivatives bind to these high-affinity receptors. Gastrin exhibits a 500 to 1000 times weaker binding. CCK-B receptors are found in the cerebral cortex and in the central nervous system. They have a tenfold higher preference for sulfated than for nonsulfated CCK derivatives. A third class of receptors termed the gastrin receptors are found on the parietal cells and the gastrointestinal smooth muscles. They have about the same affinities for sulfated and nonsulfated CCK derivatives [1273].

Binding of CCK to pancreatic receptors leads to an up regulation of the CCK receptors [1274]. In newborn rats, the number of CCK receptors is increased by hydrocortisone [1275]. The CCK receptors on rat pancreatic acini are increased fourfold in diabetic rats [1276].

Selective ligands for the CCK-A receptor are described in [1277]. Selective ligands for the CCK-B receptor are described in [1278][1279][1280][1281][1282].

  Biological Effects. The activity spectrum of CCK was mainly studied with synthetic CCK-8 (sincalide) and CRL (ceruletide).

Receptor activation leads to the breakdown of phosphoinositides, mobilization of cellular calcium, activation of protein kinase C, and the phosphorylation of intracellular proteins.

The most important physiological effects of CCK are the CCK-A-receptor-mediated stimulation of bile flow [1283] (contraction of the gallbladder, relaxation of the bile duct and the Oddi sphincter), the exocrine pancreatic secretion [1284], [1285], and potentiation of the secretin-induced exocrine pancreatic secretion. The CCK-8-induced contraction of the gallbladder is increased in patients suffering from constipation and lowered in patients with diarrhoea [1286] and celiac disease [1287]. VIP and secretin potentiate the effect of CCK on the gallbladder and pancreas. Somatostatin [1288] and atropine [1289] inhibit the CCK-induced contraction of the gallbladder.

cAMP is activated in CCK-induced relaxation. In contractions, cGMP is activated and intracellular calcium and acetylcholine are released [1290].

Other CCK-A-receptor-mediated effects include decreased food intake in rats after peripheral injection of CCK-8 [1291], trophic effects on the pancreas [1292], increased insulin and glucagon secretion in mice [1293], inhibition of pentagastrin-stimulated gastric acid secretion [1294], and increased dopamine efflux in rat brain [1295].

CCK-B-receptor-mediated effects are CCK/opiate interactions [1296] and anxiety [1279]. CCK has an analgesic effect through -opioid receptors via the release of endogenous opioids [1297] but it reduces morphine- or -endorphin-induced analgesia [1298] via -receptors [1299].

Other effects of CCK include relaxation of the corpus of the stomach and the lower esophageal sphincter, contraction of the pylorus and prolongation of the time required to empty the stomach, increase in motility from the distal part of the duodenum up to the rectum [1300], stimulation of gastric acid secretion, and inhibition of the gastrin-stimulated secretion of gastric acid.

Structure – Activity Relationships. The C-terminal octapeptide of CCK (CCK-8) has the full activity spectrum of CCK. The C-terminal heptapeptide CCK-7 and CRL-(4 – 10) [1301] are required for CCK activity. In vivo, deamino1-CCK-7 has the same protein secretory activity as CCK-7, but is more effective in contracting the gallbladder than CCK-7. CCK-6 has no activity.

The sulfated tyrosine residue is important for binding to CCK-A receptors and the activity spectrum of CCK and CRL. The activity of desulfated CCK-8 resembles that of gastrin [1302]. The substitution of Phe(CH2SO3H) for Tyr(SO3H) gives more stable, highly active derivatives [1303]. If the N-terminal Tyr(SO3H) in CCK-7 is replaced by a 3-(4-sulfoxyphenyl)-2-methylpropanoyl group, the analgesic activity is about five times that of CCK-7 [1259].

Met3 in CCK-8 is not essential for activity and can be replaced by Leu or Thr; Met6 can only be replaced by Nle without loss of activity. Thus, Arg-[Thr3,Nle6]CCK-8 [1304] and Boc-[Nle3,6]CCK-8-(2 – 8) [1305] are stable to oxidation and fully active.

Gly4 can be replaced by d-amino acids. [d-Ala4]CCK-8 and [d-Trp4]CCK-8 are almost as active as CCK-8, but they are stable to brain proteases and act longer [1306].

The effect of Boc-[Nle3--(COCH2)Gly4]CCK-8-(2 – 8) on the release of amylase from dispersed rat pancreatic acini is about the same as that of CCK-8, but it also has a central antagonistic effect [1307].

[-Asp7]CCK-8 loses its cholecystokinin properties but retains its pancreozymin activity. The substitution of Ser(SO3H), Thr(SO3H), or Hyp(SO3H) for Asp7 in Ac-CCK-8-(2 – 8) gives preparations that have 2 – 3 times the activity of CCK-8 on isolated strips of gallbladder [1308].

Phe8 can be replaced by 3-(2-naphthyl)alanine or by 3-cyclohexylalanine without loss of activity [1309].

The C-terminal amide function is very important for the activity of CCK peptides [1310]. CCK receptor antagonists are obtained by deleting C-terminal amino acids. The shortest active fragment is CCK-8-(1 – 5) [1311]. Stronger antagonists are succinyl–CCK-8-(2 – 7)2-phenethylamide [1312] and Boc-[d-Trp5,Nle6]CCK-8-(2 – 7)2-phenethyl ester [1313]. Surprisingly strong antagonists are also obtained by substituting d-Orn(Z) for Met 6 in CCK-8 [1282].

Relatively simple derivatives of glutamic acid and tryptophan act as CCK antagonists [1314]. Examples are the inhibitor of acid secretion proglumide (N-benzoyl-l-glutamic acid--dipropylamide; Milid, Offermann), lorglumide (CR-1409, 3,4-dichlorobenzoyl-Glu-dipentylamide), loxiglumide (CR-1505, 3,4-dichlorobenzoyl-Glu-pentyl-3-methoxypropylamide), and 4-chlorobenzoyltryptophan (benzotript) [1315].

Strong CCK antagonists are asperlicin, a nonpeptide component of Aspergillus alliaceus, and its benzodiazepine variants, devazeptides (MK-329  =  L-364,718), L-365,260, trifluadom, and L-156,440. L-365,260 preferentially binds to CCK-B receptors, the others bind to CCK-A receptors [1314].

  Uses. CCK-8 (sincalide, Squibb – Heyden) [25126-32-3], and CRL (ceruletide; Takus, Farmitalia) [17650-98-5] [1281] are used in X-ray diagnostics and in the diagnosis of pancreatic function. Their administration halves the time required to pass the small intestine and thus permits quick examination of the intestine with an oral contrast medium. Ceruletide is used therapeutically in postoperative intestinal atonia and paralytic ileus because of its stimulating effect on the small intestine.

Ceruletide can be employed for the expulsion of gallstones [1316] and in biliary colic [1317]. Sincalide and ceruletide (nasal application three times daily, 100 µg) alleviate chronic pancreatitis [1318]. Clinical reports confirm the analgesic properties of CCK-8 [1319].

  6.3. Gastrin Releasing Peptide and Bombesin
  Occurrence. Gastrin releasing peptide (GRP) [80043-53-4], Mr 2859 (h-GRP), is a peptide amide consisting of 27 amino acids and has been isolated from the gastric tissue of pigs, chicken, and dogs and from human lung tumors [1320]. Its C-terminal heptapeptide is identical to that of bombesin. Bombesin (BB) [31362-50-2], Mr 1620, 14 amino acids, is a peptide amide from the skin of the frog Bombina bombina. Alytesin, litorin, and ranatensin are peptides with related structure and activity that have been isolated from amphibians (frog) [1321].

The neuromedins B, B-32, B-30, and C have been isolated from the brain and spinal cord of the pig; p-neuromedin C corresponds to the C-terminal decapeptide of p-GRP.

Immunoreactive GRP has been found in the central nervous system and peripheral tissue (e.g., gastrointestinal tract). Material similar to GRP-(14 – 27) has been found in endocrine tumors [1322] and cow\'s milk [1323].

  Release. Electrical stimulation of the vagus increases formation of GRP in the pancreas [1324]. The -adrenergic stimulation of gastrin and somatostatin appears to be mediated by GRP [1325].

Receptors. At least two different types of receptor are assumed for GRP, BB, and the neuromedins. BB and GRP bind to pancreatic acinar cells and murine 3T3 cells with high affinity, while neuromedin B binds with low affinity. The esophageal mucosa possesses receptors which have a high affinity for neuromedin B, but a low affinity for GRP. The GRP antagonist [d-Phe6]BB-(6 – 13)OEt binds preferably to the pancreas, while [Tyr4,d-Phe12]BB and the SP antagonists [d-Pro4,d-Trp7,9,10]SP-(4 – 11) and [d-Arg1,d-Trp7,9,Leu11]SP bind better to the esophagus than to the pancreas [1326].

  Biological Effects. BB and GRP have similar effects. In healthy persons, a BB infusion increases the plasma levels of gastrin, CCK, motilin, pancreatic peptide, vasoactive intestinal peptide, gastrin inhibiting peptide, glucagon, insulin, and trypsin [1327], as well as the plasma level of gonadoliberin-stimulated lutropin and follitropin [1328]. The blood glucose level is lowered and plasma Ca2+ levels are raised. Somatostatin inhibits BB-induced hormone secretion [1329]. In healthy test persons, the food-induced release of insulin [1324] and the thyroliberin-stimulated levels of thyrotropin and prolactin in the plasma are lowered by an infusion with BB [1328]. These effects are due to increased plasma somatostatin levels. Other effects of GRP/BB include stimulation of gastric acid secretion and exocrine pancreatic secretion, increase in bile flow [1330], trophic action on the gastrin-producing cells of the stomach [1331] and on the pancreas [1332], as well as autocrine growth in cancer cells [1333].

Central application of BB induces hypothermia and adrenaline release which, in turn, inhibits insulin release, and stimulates glucagon release. Other central effects are the reduction of the plasma growth hormone level [1334], stimulation of dopamine synthesis in the hypothalamus [1335], suppression of gastric acid and pancreatic secretion, and inhibition of food and liquid intake [1334].

Structure – Activity Relationships. GRP-(14 – 27) acts like BB [1336]. The C-terminal nonapeptide of BB and Ac-GRP-(20 – 27) have minimum length and maximum effect. GRP-(23 – 27) is the smallest active compound. Shortening the molecule at the C-terminus yields preparations with low affinity and activity. Acetylated peptides shortened at the N-terminus are biologically more active than the corresponding compound with a free amino group. Trp8 and His12 are very important for GRP activity.

Antagonists. [d-Phe12,Leu14]BB is a competitive BB antagonist. It inhibits in vitro BB-induced amylase secretion from guinea pig acini cells. [d-Phe12]BB and [Tyr4,d-Phe12]BB have similar activity [1337]. Introduction of d-Phe6 enhances the antagonistic activity, while d-Phe5 has no effect [1338].

BB antagonists are also formed by deleting the C-terminal methionine [1339]. Me3-C-CO-His-Trp-Ala-Val-d-Ala-His-Leu-OMe exhibits good receptor binding and inhibits mitogenesis of mice Swiss 3T3 cells.

The best (100 %) in vivo inhibition of BB-stimulated amylase secretion was produced by Me2-CH-CO-His-Trp-Ala-Val-d-Ala-His-Leu-NH-Me (ICI 216 140) [1339].

Other good de-Met-antagonists in the receptor binding assay are [d-Phe6]BB-(6 – 13)ethylamide, [d-Phe6]BB-(6 –13)propylamide [1340], Ac-GRP-(20 – 26)OEt [1341], and [d-Phe6]BB-(6 – 13)OEt [1342].

Reduction of the peptide bond between positions 13 and 14 yields potent BB antagonists, e.g., [Leu13--CH2NH-Leu14]BB [1343]. Shortening of this antagonist at the N-terminus reduces antagonistic activity. Introduction of d-Phe at position 6 and N-terminal shortening produce a compound with ten times the activity [1344].

  Uses. BB is used as a diagnostic aid in the gastrin stimulation test. For instance, patients suffering from antral gastritis have an abnormally low gastrin level after BB stimulation.

In severe chronic pancreatitis [1345] and in patients with duodenal ulcers [1346], BB increases the gastrin level to a greater extent than in healthy persons. BB increases the plasma trypsin level in healthy persons, but not in patients with pancreatic insufficiency [1347].

  6.4. Gastrin
  Occurrence. Gastrin (GT) [9002-76-0], Mr 2098 (h-GT-17), was the first gastrointestinal hormone to be structurally characterized. It is synthesized primarily in the antrum and the duodenum as prepro-GT. Immunoreactive GT has also been found in the pituitary, pancreas, and nerves. In humans, tyrosine sulfation depends on the site of synthesis and the degree of development [1348].

GT occurs in several molecular sizes: GT-34 (big gastrin), GT-17 (little gastrin), GT-14 (mini gastrin), GT-6, and GT-4. It is structurally related to the transformation protein of polyoma virus (TPPV) and the chicken antral peptide (g-AP) which stimulates gastric acid production in chickens [1349]. The main physiologically active component is GT-17. Although GT-14 has full biological activity, it only occurs in very small amounts.

A sulfated myotropic neuropeptide, leucosulfakinin, has been isolated from the head of the cockroach [1350]; its intestinal myotropic activities are similar to those of GT. Related peptides are found in other insects.


h-GT-34 *Q L G P Q G P P H L V A D P S K K-
 Q G P W L E E E E E A Y G W M D Fa
h-GT-17 *Q G P W L E E E E E A Y G W M D Fa
h-GT-14  W L E E E E E A Y G W M D Fa
  W M D Fa



  Release. The atropine-resistant secretion of GT-17 and GT-34 occurs postprandially, especially in response to protein or on stimulation of the vagus. GT is also released by the gastrin releasing peptide, bombesin, carbachol [1351], Ca2+, vitamin D3 [1352], tolbutamide [1353], PGE2 [1354], hypoglycemia [1355], amino acids and the corresponding amines [1356], inhibitors of monoamine oxidase [1357], and testosterone [1358].

The release of GT is reduced by Mg2+, acidification of the food in the antrum to pH 1.2 – 1.4 [1359], inhibitors of amino acid decarboxylases, and estrogen [1358].

In humans, the GT level rises during the day and reaches a maximum at about 6 p.m. [1360]. The plasma level of gastrin is increased in the Zollinger – Ellison syndrome (a GT-producing tumor), pernicious anemia (some patients develop autoantibodies against gastrin receptors [1361]), gastric ulcers [1360], and hyperthyroidism [1362].

  Biological Effects. GT increases the formation of cAMP and of inositol phosphates [1363] and decreases the plasma level of calcium.

In the stomach, GT increases the formation of gastric acid and pepsin and stimulates the blood circulation in the mucosa [1364]. GT-17 stimulates the secretion of gastric acid in patients with duodenal ulcers more than in healthy persons [1365]. The gastrin inhibitory peptide (GIP), somatostatin, secretin, neurotensin, glucagon, glicentin, thyroliberin, the anorexigenic peptide, cerulein, and cholecystokinin inhibit the GT-stimulated secretion of gastric acid.

The synthesis and marketing of Boc--Ala-GT-4 [5534-95-2] ( pentagastrin) a GT analogue that is fully active in humans, stimulated intensive investigation of the activity of GT. An infusion with pentagastrin, like a protein meal, increases endogenous GT, insulin, GHRH, and calcitonin, but decreases the plasma level of somatostatin (SRIH). The primary effect of pentagastrin appears to be the inhibition of SRIH release; gastrin, insulin, growth hormone, and calcitonin can then be released.

Other effects of gastrin include trophic effects on the oxyntic mucose, enterochromaffin-like cells, A-cells [1366], pancreas (potentiated by secretin [1367]), tumors of the human stomach and colon [1368], [1369], and rat pancreatic adenocarcinoma [1370]; stimulation of histamine secretion; increase in the pressure of the lower esophageal sphincter; and inhibition of the CCK-induced contraction of the pylorus.

The common C-terminal tetrapeptide amide of gastrin and CCK (GT-4, trymafan, tetrin) stimulates the endocrine secretion of insulin, glucagon, somatostatin, and pancreatic peptide. Exocrine secretion from the pancreas is primarily stimulated by the higher molecular forms of gastrin and CCK rather than by GT-4.

In healthy subjects, intravenous GT-4 causes short attacks of panic or symptoms of fear [1371]. In rats, intracerebroventricular application causes deterioration of memory [1372].

Structure – Activity Relationships. GT-34 is more potent and acts longer than GT-17 when tested in humans [1373]. The five glutamic acid residues at positions 6 – 10 in h-GT-17 are of importance for biological activity [1374].

GT-4 has the structure required for gastrin activity. The C-terminal amide is important for biological activity. Substitution of other amino acids for Asp results in substantial loss of activity. Replacement of the GT-4 amino acids by the corresponding d-amino acids decreases activity. Agonists and antagonists can be obtained by reducing the peptide bonds. Boc-[Trp1--(CH2NH)-Leu2]GT-4 is an agonist which binds more tightly to gastric mucosa cells than Boc-GT-4 [1375]. Trp1 is not required for the insulin-releasing activity of GT-4, it can be replaced by l- or d-Orn [1376]. [Pro2]GT-4 is more effective than GT-4 in releasing insulin from isolated islet cells of the rat pancreas [1377].

Very potent analogues are obtained by N-terminal extension of GT-4; pentagastrin in which GT-4 is extended by Boc--alanine is the best known. Glutaroyl-[Leu5]GT-7 (deglugastrin) is more active by a factor of about two. Peptides having a GT-4 or GT-6 structure with a glycosylated N-terminal amino group have a higher water solubility combined with excellent biological activity.

Oxidation of Met causes loss of gastrin activity. However, both Met residues of GT-7 can be replaced (e.g., by Leu) without loss of activity.

Antagonists. C-terminal GT sequences that lack the C-terminal Phe-amide inhibit GT activity (e.g., BocGT-8-(1 – 7)amide). The smallest antagonistic sequence is Boc-Trp-Met-Asp-amide [1378]. Somewhat stronger antagonists are obtained by substituting -homoaspartic acid for Asp, e.g., Boc-Trp-Leu--homo-Asp-Phe-amide [1379].

Antagonists are also obtained by reducing the peptide bond between Leu and Asp [1375].

  Uses. Pentagastrin (Gastrodiagnost, Merck) is used as a diagnostic aid to determine the maximal stimulation of gastric acid secretion.

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