Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholecystokinin (CCK) receptors are currently divided into at least two subtypes: a CCK-A subtype, responsive to the sulfated form of cholecystokinin octapeptide (CCK-8) and selectively antagonized by L-364,718, and a CCK-B subtype, which shares equal affinities for gastrin and CCK-8. In the present study the receptor subtype that mediates guinea pig ileal secretion by evaluating the potencies of CCK- and gastrin-related peptides to evoke increases in transmucosal short-circuit current was characterized. The antagonist potencies of L-365,260 (CCK-B selective) and L-364,718 (CCK-A selective) against CCK-8 were also determined. Both CCK-8 and cerulein, when added to the serosal side of the tissue, evoked increases in the short-circuit current, having EC50 values of 0.8 and 0.2 nmol/L, respectively. Desulfated (SO3) CCK-8, CCK-4, gastrin17-I, pentagastrin, gastrin17-II, and gastrin13-I were relatively weak agonists (EC50 greater than 1000 nmol/L. Cholecystokinin octapeptide-induced short-current responses were competitively antagonized by L-364,718 (pA2, 10.3) and L-365,260 (pA2, 7.4). The high selectivity of the tissue for sulfated CCK-8 suggests that the secretory effect of CCK-8 on guinea pig ileal electrolyte transport is mediated by a CCK-A receptor. The potent effect of L-364,718 against CCK-8 is also consistent with an action at the A-subtype receptor.
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PMID:Cholecystokinin-mediated ileal electrolyte transport in the guinea pig. Characterization of receptor subtype. 193 14

To characterize directly the ability of cholecystokinin (CCK) to interact with receptors on the sphincter of Oddi (SO), we measured binding of 125I-labeled Bolton-Hunter-labeled COOH-terminal octapeptide of cholecystokinin (125I-BH-CCK-8) to tissue sections from the guinea pig SO. Autoradiography localized binding of 125I-BH-CCK-8 over the SO smooth muscle layer. Binding was saturable, specific, dependent on time, pH, and temperature, and was reversible. Binding of 125I-BH-CCK-8 was inhibited by various CCK receptor agonists with the following potencies: CCK-8 much greater than des(SO3)CCK-8 much greater than gastrin-17-I and by various CCK receptor antagonists with the following potencies: L-364,718 greater than proglumide analogue 10 much greater than carbobenzoxy-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-NH2 greater than N2,O2' dibutyryl guanosine 3',5'-cyclic monophosphate. The potencies of agonists in stimulating and of antagonists in inhibiting CCK-8-stimulated SO contractions correlated closely with their abilities to inhibit binding of 125I-BH-CCK-8. Analysis of binding of 125I-BH-CCK-8 to SO tissue sections revealed two classes of CCK binding sites: a high-affinity site [dissociation constant (Kd) 0.2 nM] and a low-affinity site (Kd 70 nM). Atropine or tetrodotoxin (TTX) caused a similar rightward shift of the CCK-8 dose-response curve for stimulation of SO contraction. Comparison of receptor occupation to CCK-8-induced contraction suggested that CCK-8 occupation of the high-affinity binding site correlated with contraction in the absence of atropine and the low-affinity CCK binding with contraction in the presence of atropine or TTX.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of cholecystokinin receptors on the sphincter of Oddi. 224 Feb 27

For inhibition of binding of 125I-Bolton-Hunter-labeled cholecystokinin octapeptide (125I-BH-CCK-8) to guinea pig pancreatic acini, the potencies for agonists were CCK-8 greater than desulfated [des(SO3)] CCK-8 greater than gastrin-17-I greater than pentagastrin greater than CCK-4 and for the antagonists L 364718 greater than proglumide analogue 10 greater than CBZ-CCK-(27-32)-NH2. For all non-sulfated agonists, the curves were biphasic with 20% of the tracer bound to sites with high affinity for these agonists with the following relative potencies: gastrin-17-I greater than pentagastrin greater than des(SO3)CCK-8 much greater than CCK-4; whereas 80% was bound to low-affinity sites with the following potencies: des(SO3)CCK-8 greater than gastrin-17-I = pentagastrin much greater than CCK-4. For L 364718 and proglumide analogue 10, 80% of 125I-BH-CCK-8 was bound to sites with high affinity for these antagonists and 20% to sites with low affinity. Analysis of the dose-inhibition curve for CCK-8 demonstrated two binding sites; however, comparison with the analysis in the presence of 0.1 microM gastrin-17-I suggested three binding sites. The gastrin-17-I dose-inhibition curve was significantly better fit by a three-site model than by a two-site model. The affinities of the various agonists and antagonists for the three sites were compared with their abilities to inhibit binding of 125I-gastrin-I and either stimulate or inhibit CCK-8-stimulated amylase release. These results demonstrate that 125I-BH-CCK-8 binds to three classes of receptors, not two as reported previously. Two classes are CCK-preferring, bind 83% of 125I-BH-CCK-8 at tracer concentrations, and comprise high- and low-affinity CCK-preferring sites that can be distinguished by all agonists but have equally high affinity for L 364718 and proglumide 10. A third class binds 17% of the tracer, cannot be differentiated from high-affinity CCK-preferring receptors by CCK-8, and has low affinities for L 364718 and proglumide 10. Future studies relating binding of 125I-BH-CCK-8 to biological activity or characterization of the CCK receptor by using radiolabeled agonists should consider CCK interaction with three receptors, not two as was done in the past.
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PMID:Pancreatic receptors for cholecystokinin: evidence for three receptor classes. 230 86

We have purified an acidic octapeptide from the neural ganglion of the protochordate Ciona intestinalis by a three-step procedure including C18 Sep-Pak fractionation, MonoQ ion-exchange chromatography, and C4 reversed-phase high-performance liquid chromatography. The purification was monitored by an immunoassay specific for the alpha-carboxyamidated COOH terminus common to the mammalian brain-gut hormones, cholecystokinin and gastrin. Automated Edman degradation revealed the sequence Asn-Tyr-Tyr-Gly-Trp-Met-Asp-Phe. In accordance with the high acidity of the peptide, amino acid analysis after cleavage with aminopeptidase M showed that both tyrosyl residues are sulfated. Hence, the structure is Asn-Tyr(SO3)-Tyr(SO3)-Gly-Trp-Met-Asp-Phe-NH2, as also confirmed by identity with the synthetic disulfated peptide in different chromatographic systems. The occurrence of two consecutively sulfated tyrosyl residues after a neutral residue challenges present concepts of consensus sites for tyrosyl sulfation. We conclude that the structure of the peptide, named cionin, suits that of a common ancestor for cholecystokinin and gastrin.
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PMID:Cionin: a disulfotyrosyl hybrid of cholecystokinin and gastrin from the neural ganglion of the protochordate Ciona intestinalis. 230 39

Smooth muscle cells isolated from the longitudinal muscle layer of guinea pig ileum were used to determine the presence and type of cholecystokinin/gastrin receptor mediating contraction. This was accomplished with a series of cholecystokinin and gastrin agonists (CCK-8, des(SO3)CCK-8, gastrin-17, des(SO3)gastrin-17 and pentagastrin) and antagonists (glutaramic acid derivatives CR 1392, CR 1409, CR 1505 and proglumide). The order of potency of agonists based on EC50 values derived from concentration-response curves was: CCK-8 greater than des(SO3)CCK-8 greater than gastrin-17 greater than des(SO3)gastrin-17. The inhibitory dissociation constant (Ki) for the antagonist CR 1505 derived from Schild plots was the same whether sulfated CCK-8 or desulfated gastrin-17 was used as agonist (4.47 +/- 0.76 versus 4.68 +/- 0.78 nM). Pentagastrin acted as a partial agonist and inhibited partially the response to CCK-8. The Ki values determined for all antagonists with pentagastrin as agonist were similar to those with CCK-8 as agonist. The order of potency of agonists and the independence of Ki values from the type of agonist used implied that CCK and gastrin interact with one receptor type; the receptor is more sensitive to CCK-8 but is minimally influenced by sulfation of the tyrosine residue. In this respect, the receptor appears to be distinct from the CCK receptor on gallbladder muscle cells and pancreatic acinar cells.
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PMID:Receptor type for cholecystokinin on isolated intestinal muscle cells of the guinea pig. 237 45

Recent studies have demonstrated gastrin receptors in some pancreatic tumors and that gastrin is a potent stimulant of pancreatic Na+-H+ exchange. In the present study we used 125I-labeled gastrin (125I-gastrin) to characterize gastrin receptors on guinea pig pancreatic acini. Binding of 125I-gastrin was temperature dependent, saturable, and specific for gastrin-related peptides. Analysis demonstrated a single class of receptors with high affinity for gastrin (Kd = 1.5 nM) and a binding capacity of 1 fmol/mg protein. Binding of 125I-gastrin was inhibited with the following relative potencies (Kd): cholecystokinin octapeptide (CCK-8) (0.35 nM) greater than gastrin-17-I = gastrin-34-I (1.5 nM) greater than pentagastrin (7 nM) greater than desulfated [des(SO3)]CCK-8 (28 nM) greater than CCK-4 (508 nM) and by the receptor antagonists CBZ-CCK-27-32-NH2 (3.5 microM) greater than proglumide analogue 10 (30 microM) greater than asperlicin (265 microM) greater than Bt2-guanosine 3',5'-cyclic monophosphate (828 micron). In contrast, for both stimulation of enzyme secretion and inhibition of binding of 125I-CCK-8 the relative potencies were CCK-8 much greater than des(SO3)CCK-8 greater than gastrin-17-I = gastrin-34-I greater than pentagastrin greater than CCK-4. For each receptor antagonist the dose-inhibition curve for gastrin-stimulated amylase release was superimpossible with that for CCK-8-stimulated amylase release. Gastrin-17-I at concentrations less than 0.1 microM did not potentiate carbachol or vasoactive intestinal peptide-stimulated amylase secretion and did not affect basal or stimulated adenosine 3',5'-cyclic monophosphate or 45Ca outflux.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of gastrin receptors on guinea pig pancreatic acini. 244 88

We investigated the importance of sulfation of gastrin or cholecystokinin (CCK) on influencing their affinity for gastrin or CCK receptors by comparing the abilities of sulfated gastrin-17 (gastrin-17-II), desulfated gastrin-17 (gastrin-17-I), CCK-8 and desulfated CCK-8 [des(SO3)CCK-8] to interact with CCK or gastrin receptors on guinea pig pancreatic acini. For inhibiting binding of 125I-gastrin to gastrin receptors, gastrin-17-II (Kd 0.08 nM) greater than CCK-8 (Kd 0.4 nM) greater than gastrin-17-I (Kd 1.5 nM) greater than des(SO3)CCK-8 (Kd 28 nM). For inhibiting binding of 125I-Bolton Hunter-labeled CCK-8 to CCK receptors the relative potencies were: CCK-8 much greater than des(SO3)CCK-8 = gastrin-17-II greater than gastrin-17-I. Each peptide interacted with both high and low affinity CCK binding sites. The relative abilities of each peptide to interact with high affinity CCK receptors showed a close correlation with their abilities to cause half-maximal stimulation of enzyme secretion. These results demonstrate that, in contrast to older studies, sulfation of both CCK and gastrin increase their affinities for both gastrin and CCK receptors. Moreover, the gastrin receptor is relatively insensitive to the position of the sulfate moiety, whereas the CCK receptor is extremely sensitive to both the presence and exact position of the sulfate moiety.
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PMID:Importance of sulfation of gastrin or cholecystokinin (CCK) on affinity for gastrin and CCK receptors. 247 32

Caerulein, gastrin, and C-terminal fragments of cholecystokinin (CCK) varying in length from eight (CCK-8) to four (CCK-4) amino acids stimulate pepsinogen secretion from dispersed chief cells prepared from guinea pig stomach. C-terminal fragments of CCK containing fewer than four amino acids, even when tested at concentrations as high as 3 mM, do not stimulate pepsinogen secretion. The efficacies of gastrin and the various CCK-related peptides, coupled with the pattern of action of CCK receptor antagonists, indicate that chief cells from guinea pig stomach possess two functionally distinct classes of receptors, C-receptors and G-receptors. The C-receptors can be occupied by caerulein, CCK-8, CCK-7, des(SO3)CCK-8, or des(SO3)CCK-7, and occupation of C-receptors causes full stimulation of pepsinogen secretion. G-receptors can be occupied by gastrin I, gastrin II, CCK-6, CCK-5, or CCK-4, and occupation of G-receptors causes stimulation of pepsinogen secretion that is 60% of maximal.
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PMID:Functionally distinct receptors for cholecystokinin and gastrin on dispersed chief cells from guinea pig stomach. 283 29

To compare receptors for cholecystokinin (CCK) in pancreas and gallbladder, we measured binding of 125I-Bolton-Hunter-labeled CCK-8 (125I-BH-CCK-8) to tissue sections from guinea pig gallbladder and pancreas under identical conditions. In both tissues, binding had similar time-, temperature-, and pH dependence, was reversible, saturable and inhibited only by CCK related peptides or CCK receptor antagonists. Autoradiography localized 125I-BH-CCK-8 binding to the smooth muscle layer in the gallbladder. Binding of 125I-BH-CCK-8 to gallbladder sections was inhibited by various agonists with the following potencies (IC50):CCK-8 (0.4 nM) greater than des(SO3)CCK-8 (0.07 microM) greater than gastrin-17-I (1.7 +/- 0.3 microM) and by various receptor antagonists with the following potencies: L364,718 (1.5 nM) greater than CR 1409 (0.19 microM) greater than asperlicin = CBZ-CCK-(27-32)-NH2 (1 microM) greater than Bt2cGMP (120 microM). Similar potencies were found for the agonists and antagonists for pancreas sections. Inhibition of binding of 125I-BH-CCK-8 by 11 different analogues of proglumide gave similar potencies for both pancreas and gallbladder. The potencies of agonists in stimulating and antagonists in inhibiting CCK-stimulated contraction or amylase release correlated closely with their abilities to inhibit 125I-BH-CCK-8 binding to gallbladder or pancreas sections or acini, respectively. The present results demonstrate and characterize a method that can be used to compare the CCK receptors in guinea pig gallbladder and pancreas under identical conditions. Moreover, this study demonstrates that gallbladder and pancreatic CCK receptors have similar affinities for the various agonists and antagonists tested and, therefore, provides no evidence that they represent different subtypes of CCK receptors that can be distinguished pharmacologically.
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PMID:Cholecystokinin receptors on gallbladder muscle and pancreatic acinar cells: a comparative study. 317 48

Recently, glycine-extended processing intermediates of progastrin were identified in porcine stomach using a radioimmunoassay with conventional polyclonal antisera developed against a synthetic peptide analogue for progastrin processing intermediates, gastrin 6-G(Tyr-Gly-Trp-Met-Asp-Phe-Gly). We developed monoclonal antibodies specific for glycine-extended processing intermediates of progastrin (gastrin G). Monoclonal antibody 109-21 appeared to require the carboxyl-terminal pentapeptide structure of gastrin 6-G for maximal binding. Cross-reactivities of 109-21 against gastrin 17 I, gastrin 17 II, cholecystokinin-octapeptide, des(SO3) cholecystokinin-octapeptide, and gastrin 6-G-R-R were respectively 1%, less than 0.1%, less than 0.1%, 0.1%, and 0.5%. With this monoclonal antibody and a polyclonal gastrin antibody we examined the concentrations of gastrin and gastrin G in tissue and the effects of bombesin on the release of gastrin and gastrin G from rat antral mucosa in tissue culture. The gastrin G to gastrin ratio was 2.2 in rat antral mucosa and 0.66 in rat duodenal mucosa. In tissue culture, bombesin significantly stimulated gastrin and gastrin-G secretion at doses of 10(-8) and 3 X 10(-8) M. Atropine (10(-6) M) abolished the actions of carbachol to stimulate gastrin and gastrin-G secretion but had no effect on bombesin-stimulated gastrin and gastrin-G secretion. These results suggest that gastrin G is cosecreted with gastrin in response to carbachol and bombesin, and the stimulation of gastrin and gastrin-G secretion by bombesin does not involve cholinergic neural pathways and may reflect a direct action on gastrin cells.
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PMID:Effects of bombesin on the release of glycine-extended progastrin (gastrin G) in rat antral tissue culture. 359 69


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