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)

1. Gastrin stimulates rat stomach ECL cells to secrete histamine and pacreastatin, a chromogranin A (CGA)-derived peptide. The present report describes the effect of nine cholecystokinin2 (CCK2) receptor antagonists and one CCK1 receptor antagonist on the gastrin-evoked secretion of pancreastatin from isolated ECL cells. 2. The CCK2 receptor antagonists comprised three benzodiazepine derivatives L-740,093, YM022 and YF476, one ureidoacetamide compound RP73870, one benzimidazole compound JB 93182, one ureidoindoline compound AG041R and three tryptophan dipeptoids PD 134308 (CI988), PD135158 and PD 136450. The CCK1 receptor antagonist was devazepide. 3. A preparation of well-functioning ECL cells (approximately 80% purity) was prepared from rat oxyntic mucosa using counter-flow elutriation. The cells were cultured for 48 h in the presence of 0.1 nM gastrin; they were then washed and incubated with antagonist alone or with various concentrations of antagonist plus 10 nM gastrin (a maximally effective concentration) for 30 min. Gastrin dose-response curves were constructed in the absence or presence of increasing concentrations of antagonist. The amount of pancreastatin secreted was determined by radioimmunoassay. 4. The gastrin-evoked secretion of pancreastatin was inhibited in a dose-dependent manner. YM022, AG041R and YF476 had IC50 values of 0.5, 2.2 and 2.7 nM respectively. L-740,093, JB93182 and RP73870 had IC50 values of 7.8, 9.3 and 9.8 nM, while PD135158, PD136450 and PD134308 had IC50 values of 76, 135 and 145 nM. The CCK1 receptor antagonist devazepide was a poor CCK2 receptor antagonist with an IC50 of about 800 nM. 5. YM022, YF476 and AG041R were chosen for further analysis. YM022 and YF476 shifted the gastrin dose-response curve to the right in a manner suggesting competitive antagonism, while the effects of AG041R could not be explained by simple competitive antagonism. pK(B) values were 11.3 for YM022, 10.8 for YF476 and the apparent pK(B) for AG041R was 10.4.
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PMID:Pharmacological analysis of CCK2 receptor antagonists using isolated rat stomach ECL cells. 1038 55

The present study investigated (1) the pharmacological profile of cholecystokinin (CCK) receptor subtypes involved in the regulation of gastric pepsinogen secretion, (2) the influence of gastric acidity on peptic responses induced by CCK-8-sulfate (CCK-8S) or gastrin-I; and (3) the mechanisms accounting for the effects of CCK-like peptides on pepsinogen secretion. In anaesthetized rats, i.v. injection of CCK-8S or gastrin-I increased both pepsinogen and acid secretion. The pepsigogue effect of CCK-8S was higher than that of gastrin-I, whereas acid hypersecretion after CCK-8S was lower than that induced by gastrin-I. Peptic output following CCK-8S was partly blocked by i.v. injection of the CCK1 receptor antagonist, devazepide (-75.3%), or the CCK2 receptor antagonist, L-365,260 [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 yl)-N'-(3-methyl-phenyl)urea; -27.9%], but was fully prevented by combined administration of devazepide and L-365,260. The gastric acid hypersecretory effect of CCK-8S was enhanced by devazepide (+84.5%) and blocked by L-365,260. In contrast, the gastric secretory actions of gastrin-I were insensitive to devazepide, but abolished by L-365,260. Excitatory effects of CCK-8S and gastrin-I were not modified by vagotomy or atropine, whereas cimetidine or alpha-fluoromethylhistidine (irreversible blocker of histidine decarboxylase) partly prevented acid hypersecretion induced by both peptides without affecting their pepsigogue effects. After pretreatment with omeprazole, both CCK-8S and gastrin-I failed to stimulate acid secretion, while they increased pepsinogen output. In rats with gastric perfusion of acid solutions, CCK-8S or gastrin-I increased peptic output in a pH-independent manner either with or without pretreatment with omeprazole. Ablation of capsaicin-sensitive sensory nerves as well as application of lidocaine to the gastric mucosa failed to modify the excitatory effects of CCK-8S or gastrin-I on pepsinogen and acid secretion. Blockade of the nitric oxide (NO) synthase pathway by N(G)-nitro-L-arginine-methyl ester prevented the pepsigogue actions of both CCK-8S and gastrin-I (-61.8% and -71.7%, respectively), without affecting the concomitant increase in acid output. In addition, both these peptides significantly increased the release of NO breakdown products into the gastric lumen. The present results suggest that: (1) both CCK1 and CCK2 receptors mediate the peptic secretory responses induced by CCK-like peptides; (2) the excitatory inputs of CCK-8S and gastrin-I to chief cells are not driven through acid-dependent mechanisms or capsaicin-sensitive afferent sensory nerves; and (3) under in vivo conditions, the stimulant actions of CCK-like peptides on pepsinogen secretion are mediated, at least in part, by an increase in NO generation.
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PMID:CCK1 and CCK2 receptors regulate gastric pepsinogen secretion. 1040 53

Cholecystokinin (CCK) and gastrin (G) and their receptors (CCK1 and CCK2) are involved in multiple physiological functions. Notably, CCK1R plays a role in the regulation of food intake whereas both CCK1R and CCK2R play a role in the regulation of pancreatic endocrine function. CCK1R and CCK2R may therefore serve as pharmacological targets in diabetes and obesity and genes encoding these receptors may be candidate genes in the pathogenesis of the diseases. In this study, we used single nucleotide polymorphism analysis and allele specific amplification for mutation screening of the CCK2 receptor gene and family linkage study. Mutated receptors were constructed, expressed in COS-7 cells for analysis of their binding and functional properties. V125I-CCK2 receptor variant was found in 2 out of 18 type 2 diabetes mellitus families tested. V125I mutation co-segregated in those 2 initial families, but further association studies showed that this mutation was not associated with diabetes or early age at diagnosis of the disease. V125I-CCK2 receptor high affinity sites exhibited a 2-fold enhanced binding affinity for CCK which was correlated to a slightly increased potency in coupling to inositol phosphate production. Since CCK2 receptor is expressed in pancreatic glucagon-producing cells in humans and is involved in secretion of glucagon, an increase of binding affinity of the mutated CCK2 receptor could enhance glucagon secretion in patients bearing V125I mutation. We also characterized a mutant of the CCK1 receptor which was previously identified in an obese patient. This mutant, V365I-CCK1, demonstrated a decreased level of expression (26%) and efficacy (25%) to stimulate inositol phosphates. It can therefore be expected that in humans bearing V365I mutation, decreases in CCK1 receptor expression and coupling efficiency may affect CCK-induced regulation of satiety. Polymorphism or mutations in the CCK receptors may be involved in type 2 diabetes mellitus and obesity. However, further studies are necessary to precisely evaluate this role in humans.
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PMID:Genetic, pharmacological and functional analysis of cholecystokinin-1 and cholecystokinin-2 receptor polymorphism in type 2 diabetes and obese patients. 1177 61

To identify the teleost gastrin, CCK/gastrin family genes were isolated from puffer and flounder. The cDNA of puffer gastrin, CCK1 and CCK2 were 678, 752 and 533bp, respectively. Puffer gastrin gene consists of three exons, in contrast, CCKs consist of four exons. Flounder gastrin mRNA (526bp) was expressed in the intestine but not in the brain. It was developed synchronously with the stomach differentiation in the larval stage. The phylogenetic analysis shows that puffer and flounder gastrin classified into the vertebrate gastrin cluster and two types of CCK were probably produced by the genome duplication occurred in teleost phylogeny.
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PMID:Identification of gastrin and multiple cholecystokinin genes in teleost. 1266 7

Pancreatic secretion can be influenced by cholecystokinin (CCK) either directly via actions on acinar cells or indirectly via actions on nerves. The presence and functional roles of CCK receptors on human pancreatic acinar cells remains unclear. In the current study human pancreatic acini were isolated and then treated with CCK-8, gastrin and/or carbachol. Functional parameters were measured including intracellular [Ca2+] and amylase secretion. It was observed that human acini did not respond to CCK agonists but did respond to carbachol with robust increases in functional parameters. Adenoviral-mediated gene transfer of CCK1 or CCK2 receptors to the human cells resulted in cell responses to CCK agonists. In order to determine the reason for the lack of responsiveness of the human acini, expression of receptor mRNAs was determined using quantitative RT-PCR and localized by in situ hybridization. mRNA levels for CCK1 receptors were approximately 30 times lower than those of CCK2 receptors, which were approximately 10 times lower than those of m3 Ach receptors as measured by quantitative PCR. Neither CCK1 nor CCK2 receptors were localized in adult human pancreas by in situ hybridization. These results indicate that human pancreatic acinar cells do not respond directly to CCK receptor activation and this is likely due to an insufficient level of receptor expression.
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PMID:Human pancreatic acinar cells do not respond to cholecystokinin. 1268 76

Over-expression of cyclooxygenase-2 (COX-2) has been demonstrated to be tumorigenic in transgenic mice. Chronic treatment with NSAIDs is chemoprotective for colorectal cancer. Gastrin is a growth factor for gastric mucosa and has been shown to promote proliferation of colorectal cells. Recent studies suggest that COX-2 expression levels could mediate the growth effects of gastrin. Here, we report that gastrin increased PGE2 secretion in Swiss 3T3 cells expressing the CCK2 receptor. Gastrin dose dependently induced COX-2 protein levels in a time dependent manner. COX-2 mRNA levels were rapidly induced by a dose dependent increase in gastrin. Prior treatment of the cells with the CCK2 receptor specific antagonist, L365,260, inhibited gastrin-induced COX-2 protein and mRNA expression. Pretreatment with L364,714, the CCK1 receptor specific antagonist did not block COX-2 induction by gastrin. Inhibition of de novo protein synthesis by cycloheximide did not block COX-2 mRNA induction by gastrin. Also, gastrin-dependent COX-2 expression did not require PKC activity, activation of ERK, or transactivation of EGFR. However, co-stimulation with EGF and gastrin synergistically induced COX-2 protein and mRNA expression and PGE2 secretion. Measurements of COX-2 mRNA stability and COX-2 gene transcription reveal that EGF significantly increased the half-life of COX-2 mRNA with only a slight increase in the COX-2 transcription rate. Conversely, gastrin significantly increased COX-2 gene transcription rates but did not enhance COX-2 mRNA stability.
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PMID:Gastrin and EGF synergistically induce cyclooxygenase-2 expression in Swiss 3T3 fibroblasts that express the CCK2 receptor. 1289 2

Unlike in rodents, CCK has not been established as a physiological regulator in avian exocrine pancreatic secretion. In the isolated duck pancreatic acini, 1 nM CCK was required for stimulation of amylase secretion, maximal effect being achieved at 10 nM; picomolar CCK was without effect. Vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase activating peptide (PACAP) receptor (VPAC) agonists PACAP-38 and PACAP-27 (10(-12)-10(-7) M) alone had no effect, but made picomolar CCK effective. VPAC agonist VIP 10(-10)-10(-7) M stimulated amylase secretion marginally, but made CCK 10(-12)-10(-10) M effective also. PACAP-27 and VIP both shifted the maximal CCK concentration from 10(-8) to 10(-9) M. This sensitizing effect was mimicked by forskolin. CCK dose dependently induced intracellular Ca2+ concentration ([Ca2+]i) oscillations. PACAP-38 (1 nM), PACAP-27 (1 nM), VIP (10 nM), or forskolin (10 microM) alone did not stimulate [Ca2+]i increase, neither did they modulate CCK (1 nM)-induced oscillations; but when they were added to cells simultaneously exposed to subthreshold CCK (10 pM), calcium spikes emerged. Amylase secretion induced by the simultaneous presence of 10 pM CCK and VPAC agonists was completely blocked by removing extracellular calcium, but the protein kinase C inhibitor staurosporine (1 microM) was without effect. CCK (10 nM)-induced secretion was inhibited by CCK1 receptor antagonist FK480 (1 microM). Gastrin from 10(-12) to 10(-6) M did not stimulate amylase secretion nor did it (100 nM) induce [Ca2+]i increase. The above data suggest that duck pancreatic acini possess both CCK1 and VPAC receptors; simultaneous activation of both is required for each to play a physiological role.
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PMID:Mutual dependence of VIP/PACAP and CCK receptor signaling for a physiological role in duck exocrine pancreatic secretion. 1294 31

This study investigated the effects of PD-136,450 (PD), a highly selective ligand for the CCK2 receptor, on gastric acid and pancreatic secretions, gastric cytoprotection and anxious behaviour in the rat and rabbit. PD inhibited gastrin (but not dimaprit) stimulated acid secretion in anaesthetized and conscious rats (IC50 of 1 mg kg(-1) sc) and inhibited 14C-aminopyrine uptake in isolated gastric glands from rabbits. In addition, PD decreased dose-dependently gastric haemorrhagic lesions in rats treated orally with acidified ethanol. Both, the antisecretory effects on gastric acid secretion and the gastric cytoprotective effects were less potent compared with the proton pump inhibitor omeprazole. PD strongly increased pancreatic secretion, which was substantially inhibited by the CCK1 antagonist L-364,718 (but not by the CCK2 antagonist L-365,260). PD also showed significant anxiolytic activity as assessed by a black and white box two-compartment activity assay. Both, time spent in the dark compartment and latency for movement from the light to the dark compartment was increased by PD (similarly with 5 mg kg(-1) diazepam). In conclusion, PD inhibited gastrin-stimulated gastric acid secretion, decreased ethanol-induced damage to the gastric mucosa, stimulated pancreatic secretion (via CCK1 receptors) and displayed anxiolytic activity. Thus, PD may have utility as an adjunct therapy in peptic ulcer disease by countering the actions of gastrin and increasing acid neutralization and mucosal protection.
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PMID:PD-136,450: a CCK2 (gastrin) receptor antagonist with antisecretory, anxiolytic and antiulcer activity. 1457 79

Lipopolysaccharide (LPS) is one of the virulence factors in the Helicobacter pylori (Hp)-infected stomach, but it remains unknown whether single and prolonged pretreatment with Hp-LPS can affect the course of gastric damage induced by aspirin (ASA). We compared the effects of Hp-LPS with those induced by LPSs isolated from intestinal Bacteroides fragilis, Yersinia enterocolitica, and Campylobacter jejuni applied for 4 days on acute ASA-induced gastric lesions in rats. The area of ASA-induced gastric lesions, gastric blood flow (GBF), expression of mRNA and protein of leptin and plasma leptin, gastrin, interleukin-1beta, and tumor necrosis factor-alpha levels were examined. Single (once) or repeated (five times) i.p. injections of Hp-LPS (1 mg/kg) or intestinal LPSs failed to produce macroscopic gastric damage and did not affect the GBF when compared with vehicle. Hp-LPS injected repeatedly suppressed the gastric acid secretion, up-regulated leptin mRNA and protein, and increased plasma leptin and gastrin levels. Hp-LPS significantly reduced the ASA-induced gastric damage and the accompanying decline in the GBF, and these effects were significantly attenuated by capsaicin denervation and selective antagonism of cholecystokinin-B (CCK2) receptors by RPR-102681 [N-(metoxy-3 phenyl) N-(N-methyl N-phenyl-carbamylmethyl) carbamoylmethyl]-3 ureido]-3 phenyl]-2 propronique] but not by loxiglumide, an antagonist of CCK1 receptors. We conclude that 1) daily application of Hp-LPS enhances gastric mucosal resistance against ASA damage due to the increase of GBF and the expression and release of leptin and gastrin exerting trophic and gastroprotective effects, and 2) this enhanced resistance to ASA damage in Hp-LPS-adapted stomach is mediated by the sensory afferents and specific CCK2/gastrin receptors.
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PMID:Involvement of capsaicin-sensitive afferent nerves and cholecystokinin 2/gastrin receptors in gastroprotection and adaptation of gastric mucosa to Helicobacter pylori-lipopolysaccharide. 1502 38

The effect of luminal gastrin on the secretion of pancreatic juice was studied in seven conscious preruminant calves employing luminal infusions of gastrin and cholecystokinin (CCK)-9 and pharmacological CCK1 and CCK2 receptor blocks with antagonists. The study was performed in the preprandial and prandial states. Pharmacological blocking of the CCK2 receptor, like that of the CCK1 receptor, resulted in reduction of pancreatic postprandial secretion and increased the duration of the prandial pattern of duodenal electrical activity. Exogenous luminal gastrin, like luminal CCK-9, enhanced the secretion of pancreatic juice proteins, though the overall effect of gastrin was weaker than that of CCK-9. The effect was inhibited by infusion of CCK2 but also by CCK1 receptor antagonist. In conclusion, duodenal luminal gastrin can stimulate exocrine pancreatic secretion by a mechanism that depends on CCK2 receptors in calves. Involvement of the CCK1 receptor in this mechanism needs further investigation. Prandial pancreatic secretory and duodenal motility cycles can be regulated by endogenous gastrin release.
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PMID:The role of luminal gastrin in the regulation of pancreatic juice secretion in preruminant calves. 1512 Apr 77


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