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)

Female rats were treated orally for 13 wk with YM022 (300 mumol.kg-1.day-1) and with omeprazole (400 mumol.kg-1.day-1) or famotidine (900 mumol.kg-1.day-1) with or without YM022. At 2 h after the last dose, YM022 and omeprazole markedly inhibited basal and pentagastrin-induced acid secretion. Famotidine was less potent than YM022 and omeprazole against both secretions. The degree of increase in plasma gastrin level in the three groups was parallel to the antisecretory potencies of the drugs. At 14 days after the cessation of omeprazole treatment, the secretory response to pentagastrin increased above that of the control. This hyperresponse lasted for > or = 56 days. In the famotidine-treated group, a small increase in secretory response to pentagastrin was observed but was not statistically significant. The increase in secretory response to pentagastrin was paralleled by an increase in mucosal cell mass. In contrast, YM022 not only exhibited a long-lasting inhibition of pentagastrin-induced acid secretion but also prevented the hyperresponse to pentagastrin caused by omeprazole. These results indicate that the hypergastrinemia caused by long-term administration of antisecretory drugs increases mucosal secretory response to pentagastrin through a gastrin/cholecystokinin B receptor-mediated pathway in rats.
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PMID:Gastrin receptor antagonist YM022 prevents hypersecretion after long-term acid suppression. 749 61

Glycine-extended gastrin (gastrin-Gly) stimulates proliferation of AR4-2J pancreatic tumor cell line through a specific receptor, different from the gastrin-cholecystokinin B receptor. Our purpose was to determine whether AR4-2J cells produced gastrin-Gly and then whether the peptide was involved in an autocrine loop. First, proliferation of AR4-2J cells in serum-free medium was inhibited by a gastrin anti-sense oligodeoxynucleotide phosphorothioate and by antibodies specific for gastrin-Gly. In contrast, antibodies specific for alpha-amidated gastrin were without effect. By using RT-PCR, we have shown that AR4-2J cells expressed gastrin mRNA. The presence of gastrin-Gly, but not alpha-amidated gastrin, in serum-free media was detected by radioimmunoanalysis. Gel chromatography revealed that the predominant molecular forms secreted were glycine-extended gastrin-34 and gastrin- 17. Furthermore, epidermal growth factor (EGF), a stimulator of gastrin gene transcription, modulates gastrin-Gly secretion by AR4-2J. These data together suggest that gastrin-Gly is an autocrine growth factor for AR4-2J cells and that it participates with EGF in the regulation of AR4-2J-cell proliferation.
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PMID:Autocrine stimulation of AR4-2J rat pancreatic tumor cell growth by glycine-extended gastrin. 864 28

Animals or human subjects receiving brain stimulation in the dorsal periaqueductal gray matter (dPAG) show sudden fear-suggestive behavioral reactions and physical signs of autonomic activation which are reminiscent of the symptom profile characterizing a panic attack. An experimental situation in rats measuring dPAG stimulation self-interruption thresholds has been validated as realistically simulating several aspects of panic anxiety with objective signs of symptomatic and predictive validity using established antipanic and panicogenic agents; it was utilized here to evaluate the effects of various cholecystokinin B receptor ligands. A dose-dependent increase in self-interruption thresholds (antipanic-like effect) was recorded following injection of L-365,260 (3.2, 10 and 32 mg/kg i.p.), a CCKB receptor antagonist with good brain penetration, whereas no significant changes in thresholds were recorded following CI-988 (3.2, 10 and 32 mg/kg i.p.), a dipeptoid CCKB receptor antagonist with poor brain penetration. Latencies for self-interruption were not modified, suggesting that motor functions remained intact. No significant changes in self-interruption thresholds were recorded following peripheral administration of the CCKB receptor agonists CCK4 (0.03 to 0.32 mg/kg i.v.; 0.01 to 3.2 mg/kg i.p.) or the metabolically stabilized analog Boc-CCK4 (0.1 to 10 mg/kg i.p.). Systemic administration of the panicogenic compounds caffeine and yohimbine enhance acute anxiety in this model. These data indicate that, in the dPAG simulation of panic anxiety, central CCKB receptor blockade by L-365,260 induces antiaversive effects analogous to those observed following benzodiazepine receptor activation by clonazepam or alprazolam. Potency and efficacy of L-365,260 were lower than those of clonazepam or alprazolam, suggesting modest, but nonetheless authentic, antiaversive properties for this CCKB receptor antagonist. Lack of effects observed following peripheral administration of the agonists CCK4, and Boc-CCK4 or of the dipeptoid antagonist CI-988 is likely to reflect restricted brain penetration of those compounds in rats; it furthermore excludes a contribution of peripheral gastrin and CCKA receptors to the antipanic-like properties of selective CCKB receptor antagonists such as L-365,260.
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PMID:Behavioral effects of CCKB receptor ligands in a validated simulation of panic anxiety in rats. 898 12

The CCK and gastrin families of peptides act as hormones and neuropeptides on central and peripheral receptors to mediate secretion and motility in the gastrointestinal tract in the physiological response to a normal meal. Thus far, two CCK receptors have been molecularly identified to mediate the actions of CCK and gastrin, CCK-A and CCK-B receptors (CCK-AR and CCK-BR, respectively). The regulation of CCK-AR and CCK-BR affinity by guanine nucleotides and the receptor activation of G protein-dependent stimulation of phospholipase C and adenylyl cyclase suggested that they were guanine nucleotide-binding protein-coupled receptors [G protein-coupled receptors (GPCRs)]; however, the eventual cloning of their cDNAs revealed their heptahelical structure and confirmed their membership in the GPCR superfamily. The gastrointestinal system is a rich source of neuroendocrine hormones that interact with a large number of GPCRs to regulate the complex tasks of digestion, absorption, and excretion of a meal. This article focuses on the CCK family of GPCRs, and its activities in the gastrointestinal system.
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PMID:G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: an exemplary family. 957 40

To understand molecular basis of Gs coupling to cholecystokinin (CCK)-A and CCK-B receptor subtypes, we examined cAMP responses in three sets of human CCK receptor mutants expressed in human embryonic kidney (HEK)293 cells. Single or double substitutions of the four nonconserved amino acids in the first intracellular loop of the CCK-BR were made with their CCK-AR counterparts to determine which residues are critical in Gs coupling. Single substitution of Ser82 to Asn, produced maximal cAMP responses comparable with the chimeric CCK-BR containing the entire first intracellular loop of the CCK-AR. Two other single substitutions, Leu81 to Arg and Leu85 to Met, produced significant but smaller cAMP responses. Ser82 was further changed into Asp, Thr, or Ala to determine the specificity of this position in Gs coupling by the CCK-BR. Replacements of Ser to Asp or Thr showed significant cAMP increases but the stimulatory effects were smaller than Ser to Asn, whereas Ser to Ala did not enhance any cAMP response to either CCK or gastrin. Finally, CCK-AR reverse mutants were studied to compare them with their corresponding CCK-BR mutants that showed increased cAMP responses. Substitution of CCK-AR residue Arg68 to Leu resulted in a complete loss of cAMP response, whereas Asn69 to Ser or Met72 to Leu showed markedly diminished cAMP responses. These data identify that specific residues in the first intracellular loop of both CCK receptor subtypes are critical for Gs coupling. Substitution of a single residue Ser82 to Asn in the CCK-BR is sufficient to confer full cAMP responses to agonist stimulation.
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PMID:Single amino acid substitution of serine82 to asparagine in first intracellular loop of human cholecystokinin (CCK)-B receptor confers full cyclic AMP responses to CCK and gastrin. 1022 May 57

Gastric enterochromaffin-like cells produce histamine in response to the antral hormone gastrin and accumulate the biogenic amine in secretory organelles via vesicular monoamine transporter subtype 2. The putative effects of gastrin on vesicular monoamine transporter subtype 2 expression and promoter activity are poorly understood. In the present study we used highly enriched rat enterochromaffin-like cells (purity, >90%) and rat pheochromocytoma cells stably transfected with a gastrin/cholecystokinin B receptor to investigate the expression and transcriptional regulation of vesicular monoamine transporter subtype 2. Stimulation of vesicular monoamine transporter subtype 2 mRNA and protein expression was observed in isolated enterochromaffin-like cells after 3- to 7-h incubation with gastrin (10(-7) M), forskolin (10(-5) M), or ionomycin (10(-5) M). Deletion analysis of the rat vesicular monoamine transporter subtype 2 promoter defined the minimal promoter sequence necessary for full basal activity as a -121 bp segment upstream of exon 1 containing two Sp1 sites (-97 to -88 bp and -68 to -59 bp) and a cAMP-responsive element (-44 to -35 bp). Gastrin (10(-7) M) stimulated extracellular signal related kinase1/2 phosphorylation, activated Sp1 and cAMP-responsive element-binding protein, and further induced activity of the complete rat vesicular monoamine transporter subtype 2 promoter (-800 bp) in gastrin/cholecystokinin B receptor cells. The -121-bp fragment was able to confer full gastrin responsiveness, and site-directed mutagenesis of the Sp1 and cAMP-responsive element motifs demonstrated their crucial importance for basal and inducible activities. Comparison of promoter activity of histidine decarboxylase, chromogranin A, or vesicular monoamine transporter subtype 2 in transfected cell lines revealed significant differences in basal and gastrin-stimulated activities. Our current study provides the first evidence that gastrin directly stimulates the expression and promoter activity of vesicular monoamine transporter subtype 2. Sp1 and cAMP-responsive element-binding protein recognition motifs located within 121 bp upstream of exon 1 appear to be indispensable for full basal and inducible promoter activities. Diverging effects of gastrin on histidine decarboxylase, chromogranin A, and vesicular monoamine transporter subtype 2 promoter may account for the coordinated synthesis and storage of histamine in this neuroendocrine cell type.
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PMID:Gastrin induces expression and promoter activity of the vesicular monoamine transporter subtype 2. 1145 16

The proliferative effects of gastrin on normal and malignant gastrointestinal tissues have been shown to be mediated by a G protein-coupled receptor (GPCR), the cholecystokinin B receptor. The c-Jun NH(2)-terminal kinase (JNK) pathway has been implicated in the regulation of mitogenesis by growth factors or cytokines. However, the contribution of this signaling cascade to the proliferative effects of GPCR remains largely unknown. Here, we show that cholecystokinin B receptor occupancy by gastrin leads to the activation of the JNK pathway. The mechanism involves certain protein kinase C isoforms and Src family kinases other than p60Src. The complex p130Cas/CrkII, known to be involved in JNK activation, is also activated in response to gastrin by a protein kinase C- and Src-dependent mechanism. However, gastrin-induced CrkII and JNK pathways are independent. Using a dominant negative mutant of c-Jun, we blocked the ability of gastrin to induce DNA synthesis, demonstrating a major role of the JNK pathway in the growth-promoting effect of a GPCR agonist.
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PMID:c-Jun NH(2)-terminal kinase pathway in growth-promoting effect of the G protein-coupled receptor cholecystokinin B receptor: a protein kinase C/Src-dependent-mechanism. 1219 76

Gastrin and its precursors promote proliferation in different gastrointestinal cells. Since mature, amidated gastrin (G-17) can induce cyclin D1, we determined whether G-17-mediated induction of cyclin D1 transcription involved Wnt signaling and CRE-binding protein (CREB) pathways. Our studies indicate that G-17 induces protein, mRNA expression and transcription of the G(1)-specific marker cyclin D1, in the gastric adenocarcinoma cell line AGSE (expressing the gastrin/cholecystokinin B receptor). This was associated with an increase in steady-state levels of total and nonphospho beta-catenin and its nuclear translocation, indicating the activation of the Wnt-signaling pathway. In addition, G-17-mediated increase in cyclin D1 transcription was significantly attenuated by axin or dominant-negative (dn) T-cell factor 4(TCF4), suggesting crosstalk of G-17 with the Wnt-signaling pathway. Mutational analysis indicated that this effect was mediated through the cyclic AMP response element (CRE) (predominantly) and the TCF sites in the cyclin D1 promoter, which was also inhibited by dnCREB. Furthermore, G-17 stimulation resulted in increased CRE-responsive reporter activity and CREB phosphorylation, indicating an activation of CREB. Chromatin immunoprecipitation studies revealed a G-17-mediated increase in the interaction of beta-catenin with cyclin D1 CRE, which was attenuated by dnTCF4 and dnCREB. These results indicate that G-17 induces cyclin D1 transcription, via the activation of beta-catenin and CREB pathways.
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PMID:Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells. 1511

Enterochromaffin-like (ECL) cell has been identified as the histamine-containing argyrophil cell in rat gastric mucosa and vigorously studied. However, there are few reports of the distribution of ECL cell in human stomach. The aim of the present study was to determine the precise distribution of ECL cell by immunohistochemical staining of histidine decarboxylase (HDC) and gastrin-cholecystokinin B receptor (CCK-BR) in human stomach, and the correlation between their distribution and that of parietal cells. Thirty specimens of surgically resected stomach were used. Parietal cell, Grimelius-silver-positive cell, gastrin, HDC- and CCK-BR-immunoreactive cell were studied on continuous cell counting in the restricted field along the lamina muscularis from the oral to the anal ends. The percentage of HDC-immunoreactive cells of endocrine cells was smaller (15%) than that of a previous report (35%) in the fundic region. HDC- and CCK-BR-immunoreactive cells were found not only in the fundic region, but also in the intermediate and pyloric regions. In the pyloric region, HDC- and CCK-BR-immunoreactive cells were found mainly in the mucosa with intestinal metaplasia. Double-positive cells were also found, but only in small numbers. This suggests that ECL cell, or a cell sharing its function, is present in the pyloric region.
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PMID:Immunohistochemical study of enterochromaffin-like cell in human gastric mucosa. 1768 28

There currently are no tests available for early diagnosis or for the identification of patients at risk for development of pancreatic cancer. We report the discovery of single nucleotide polymorphism (SNP) in the cholecystokinin B receptor (CCKBR) gene predicts survival and risk of pancreatic cancer. Growth of human pancreatic cancer is stimulated by gastrin through the CCKBR and an alternatively spliced isoform of the CCKBR gene called CCKCR. One hundred and ten surgically resected benign and malignant pancreatic tissues as well as normal pancreas were prospectively evaluated for CCKBR genotype and protein expression. Analysis demonstrated the expression of the spliced isoform, CCKCR, was associated with a (SNP) (C > A) at position 32 of the intron 4 (IVS 4) of the CCKBR gene. Since the SNP is within an intron, it has not previously been identified in the GWAS studies. Only patients with the A/A or A/C genotypes, exhibited immunoreactivity to a selective CCKCR antibody. Survival among pancreatic cancer patients with the A-SNP was significantly shorter (p = 0.0001, hazard ratio = 3.63) compared with individuals with C/C genotype. Other variables such as surgical margins, lymph node status, histologic grade or adjuvant chemotherapy were not associated with survival. Furthermore, having one or two of the A-alleles was found to increase the risk of pancreatic adenocarcinoma by 174% (p = 0.0192) compared with the C/C wild type. Cancer cells transfected to overexpress the CCKCR demonstrated increased proliferation over controls. Genetic screening for this SNP may aid in early detection of pancreatic cancer in high risk subjects.
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PMID:A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer. 2227 84


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