Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A transcriptional cAMP-responsive enhancer element (CRE) consisting of the 8-base pair (bp) palindrome, 5' TGACGTCA 3', is found in several eukaryotic genes. We analyzed the effects on gene transcription of point mutations within the CRE, the influence of the bases surrounding the CRE, and the requirements for transcriptional synergism of tandemly repeated CREs. When inserted as an oligonucleotide with restriction enzyme linker sites, the 8-bp CRE itself is as active in conferring cAMP responsivity on an enhancerless chloramphenicol acetyltransferase reporter plasmid as is a single copy of the choriogonadotropin alpha (CG alpha), twice repeated 18-bp sequence containing the CRE. Point mutations in the first (T to A), fourth (C to G), or eighth (A to T) positions of the CRE, when contained within the CG alpha 18-bp sequence, each inhibited transcriptional activity greater than 90%. However, the identical eighth position A to T mutation occurs in the cAMP-responsive sequence of the vasoactive intestinal peptide (VIP) gene, and that mutant sequence in the context of the adjacent bases of the native VIP sequence is maximally cAMP responsive when inserted in the reporter plasmid. The substantially reduced activity of the core 8-bp CRE when synthesized as a cassette including the adjacent bases of the rat glucagon or bovine parathyroid hormone gene further emphasizes the restrictive influence of particular surrounding sequences. Active oligonucleotides containing the 8-bp palindrome and different but equally permissive contexts have comparable properties in transfected reporter genes and gel mobility-shift assays. The pair of tandemly repeated 18-bp elements containing the CRE in the CG alpha gene synergistically stimulate transcription either with paired native CREs or when one native CRE is paired with one mutant CRE, suggesting the presence of cooperative interactions. Tandem insertion of more than two 18-bp sequences, or insertion of additional sequences between the two CREs, inhibits transcription. These observations indicate that the contexts of the bases adjacent to CREs exert profound influences on the transcriptional activities mediated by the cAMP-responsive elements.
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PMID:Structural determinants for transcriptional activation by cAMP-responsive DNA elements. 284 37

The hypothalamic peptide vasoactive intestinal peptide (VIP) stimulates ACTH and endorphin secretion by the AtT20/D16 clonal strain of mouse pituitary tumor cells. The dose dependence for VIP stimulation of hormone release is biphasic, indicating that VIP is able to activate at least two classes of receptors in D16 cells (ED50 = 1.6 and 160 nM). We show that at high concentrations (ED50 greater than or equal to 150 nM), other natural peptides with primary structures homologous to that of VIP also increased ACTH secretion by D16 cells, whereas structurally unrelated peptides did not. The stimulatory actions of GH-releasing factor (GRF) and porcine heptacosapeptide with amino-terminal histidine and carboxy-terminal isoleucine amide (PHI) were mediated by high affinity VIP receptors because their effects were not additive with that of 10 nM VIP. In addition, GRF and PHI behaved as antagonists at low affinity VIP receptors; both peptides inhibited stimulation by 1 microM VIP. In contrast, glucagon and gastric inhibitory polypeptide appeared to stimulate ACTH release via low affinity VIP receptors because their effects were additive with that of 10 nM, but not 1 microM, VIP. Since all of the VIP-like peptides increased ACTH secretion only at high concentrations, they were unlikely to represent a physiological ligand for the receptor activated by high concentrations of VIP. Therefore, we determined whether cross-reactivity occurred between VIP-like peptides and corticotropin-releasing factor (CRF), a potent stimulator of ACTH secretion both in vitro and in vivo. The dose-response curve for CRF stimulation of ACTH secretion by D16 cells extended over more than a 1000-fold range of concentrations and was biphasic (ED50 = 2.6 and greater than 300 nM), indicating that CRF interacted with multiple receptor types in D16 cells. However, since the effect of 10 nM CRF was additive with that of 1 microM VIP, the CRF receptor was not the site at which high concentrations of VIP stimulated ACTH release. In contrast, the effect of 1 microM CRF was not additive with that of 1 microM VIP or other VIP-like peptides. Therefore, high concentrations of CRF and the previously recognized VIP-like peptides stimulated ACTH secretion by overlapping pathways. Comparison of the amino acid sequence of CRF with those of the VIP-like peptides showed that 18 of the 41 amino acids in CRF match a corresponding amino acid in at least 1 member of the VIP peptide family.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Peptide specificity for stimulation of corticotropin secretion: activation of overlapping pathways by the vasoactive intestinal peptide family and corticotropin-releasing factor. 285 86

Homologous loss of histamine H2-receptor activity (cAMP generation) was observed after short-term (10-20 min) or chronic treatment (6 days) of cultured HGT-1 cells with histamine (desensitization) or the H2-receptor antagonist SKF 93479. This inactivation process was not observed when HGT-1 cells were exposed to the classical H2-antihistamine cimetidine. The data show: (1) that the compound SKF 93479 has a very prolonged inhibitory action on histamine receptor activity, suggesting an irreversible interaction between the antagonist and the receptor; (2) that cimetidine is a reversible H2-receptor antagonist which can be removed without changing the the efficacy and the potency of histamine on gastric cells; (3) that the H2-receptor antagonists cimetidine and SKF 93479 specifically block histamine H2-receptor activity in HGT-1 cells since cAMP generation induced by other hormones such as vasoactive intestinal peptide (VIP), glucagon or gastric inhibitory peptide (GIP) was unchanged after treatment; (4) the first evidence for time-dependent (half-life: 20 min) desensitization of gastric H2-receptors.
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PMID:Selective disappearance of histamine H2-receptor activity in the human gastric cancer cell line HGT-1 after short-term or chronic treatment by histamine or its H2-antagonists. 286 31

Preganglionic nerve stimulation leads to an acute elevation of tyrosine hydroxylase (TH) activity in the rat superior cervical ganglion. This effect is mediated in part by acetylcholine, acting via nicotinic receptors, and in part by a noncholinergic neurotransmitter. As a first step in an attempt to identify this noncholinergic transmitter, we have examined a number of biogenic amines, purine nucleotides, neuropeptides, and other compounds for their ability to increase TH activity. Secretin, vasoactive intestinal peptide (VIP), and PHI (a 27-amino acid peptide with an NH2-terminal histidine and a COOH-terminal isoleucine amide), all members of the secretin family of peptides, increased TH activity acutely. Human pancreatic growth hormone-releasing factor, glucagon, and gastric inhibitory peptide (three other members of this peptide family) and all other transmitter candidates tested had no effect on this enzyme activity. We have examined the possibility that this peptidergic regulation of TH activity is mediated via changes in adenosine 3',5'-cyclic monophosphate (cAMP) levels. When the six members of the secretin family were tested for their ability to increase cAMP levels in the ganglion, secretin, VIP, and PHI significantly increased this cyclic nucleotide, whereas growth hormone-releasing factor, glucagon, and gastric inhibitory peptide produced no significant effects. The rank orders of potency and of efficacy of secretin, VIP, and PHI in altering TH activity and cAMP levels were identical. Furthermore, a strong correlation was found between the cAMP level and the TH activity in individual ganglia exposed to these peptides. Finally, 8-bromoadenosine 3',5'-cyclic monophosphate and forskolin also increased TH activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the concentration of adenosine 3',5'-cyclic monophosphate and the activity of tyrosine hydroxylase in the rat superior cervical ganglion by three neuropeptides of the secretin family. 286 28

A patient presenting clinically with the glucagonoma syndrome had high plasma glucagon levels (1920 ng/l) and at laparotomy, a pancreatic islet cell tumour was removed. The tumour was dispersed and placed in culture where it remained viable for 63 days. The tumour cells secreted immunoreactive (IR) glucagon at levels up to 2400 ng/l as detected by a C-terminal glucagon specific antibody and 85 400 ngequiv./l as measured by an N-terminal glucagon specific antibody. The difference between these two levels was attributed to the presence of different molecular forms of glucagon measured with the N-terminal specific antibody. IR insulin (up to 302 mU/l) and IR somatostatin (up to 2500 ng/l) were also detected. There was no direct or inverse correlation between different hormone levels. Small but significant levels of N-terminal and C-terminal vasoactive intestinal peptide (VIP) were detected in some cultures but there was no evidence of gastrin or ACTH. Glucagon and somatostatin secretion persisted for the duration of the culture (63 days) but insulin concentrations declined. Incubation of cultures with somatostatin (1 ng/ml) caused a 75% decrease in glucagon levels, while insulin (1000 mU/l) produced a 70% inhibition of somatostatin.
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PMID:Multiple hormone secretion by a human pancreatic glucagonoma in culture. 286 20

The blood flow of the alimentary tract in anesthetized dogs was measured with radioactively labeled 15-micron microspheres before and after i.v. application of the gastrointestinal hormones glucagon, vasoactive intestinal polypeptide (VIP), secretin, and somatostatin. After 5 min glucagon in a dose of 75 micrograms/kg bolus + 5 micrograms/kg X min-1 infusion increased significantly the blood flow in liver, stomach, duodenum, jejunum, ileum, and colon as well as the cardiac output by 160%, 761%, 662%, 576%, 817.3%, 320%, and 108%, respectively. A dose of 3 ng/kg X min-1 resulted in reduction of the circulation in liver, gastric fundus, duodenum, and colon by 27.7%, 19.1%, 16.2%, and 10.7% after 5 min while the cardiac output was not affected. Vasoactive intestinal polypeptide (VIP) infused in a dose of 3.3 pmol/kg X min-1 for 5 min increased the blood flow in the pancreas by 30% and reduced it in the spleen and gastric corpus by 26.9% and 41.5%, respectively. Secretin, another member of the glucagon family, after a 5-min infusion of a dose of 0.5 CU/kg X min-1 increased the cardiac output by 49.96% and the renal circulation by 120.7%. In the gastrointestinal tract circulation of the gastric antrum was stimulated by 474%, of the duodenum by 93.5% and of the ileal mucosa by 178%. Infusion of the pancreatic hormone somatostatin (3.5 micrograms/kg bolus followed by infusion of 3.5 micrograms/kg X h-1) increased the blood flow in the liver by 13%, in the pancreas by 23.15%, and in the spleen by 29.8%, while it reduced it in the fundic mucosa by 17.1% and corpus mucosa by 28.8%. In summary, the gastrointestinal hormones examined exert marked and distinct effects on the circulation of the gastrointestinal tract, each hormone in different parts of the digestive tract. Thus, the local microcirculation of the gastrointestinal tract seems to be subject to hormonal in addition to nerval control.
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PMID:Differential effects of gastrointestinal hormones on the blood flow of the alimentary tract of the dog. 287 7

The pathophysiological, biochemical, histological, ultrastructural, and immunohistochemical characters of a case of malignant pancreatic islet cell tumor with watery diarrhea syndrome were carefully investigated. Four hormones or mediators--somatostatin (SST), vasoactive intestinal peptide (VIP), serotonin, and prostaglandin E--were markedly elevated in the circulation. The diagnosis was further confirmed by exploratory laparotomy and autopsy. The contents of SST and VIP in tumor tissues were very high. Gel chromatography of tumor extract revealed single peaks for both SST and VIP. Immunohistochemical studies of tumor tissues showed numerous immunoreactive cells to anti-SST, moderate amount of VIP-positive cells, and a few hCG-, insulin-, and glucagon-positive cells. In conclusion, this is an unusual case of Verner-Morrison syndrome in which three kinds of bioactive hormones or mediators were simultaneously secreted; peptides, amine, and prostaglandin.
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PMID:Watery diarrhea syndrome caused by multihormonal malignant pancreatic islet cell tumor secreting somatostatin, vasoactive intestinal peptide, serotonin, and prostaglandin E--a clinicopathological, biochemical, immunohistochemical, and ultrastructural study. 288 47

Duodenal luminal acidification increases duodenal mucosal bicarbonate production and also releases both secretin and vasoactive intestinal peptide (VIP). The effect of these two structurally similar peptides on human duodenal bicarbonate production has not been examined in humans. Our purpose was therefore to assess the effect of VIP and secretin and also glucagon, a homologous hormone, on human duodenal bicarbonate secretion. A 4-cm portion of either proximal or distal duodenum was isolated and perfused with iso-osmolar NaCl. Pure porcine VIP (200 and 400 pmol/kg-h intravenously) significantly increased proximal duodenal bicarbonate secretion. Although secretin (0.01 to 0.18 CU/kg-h intravenously) markedly increased pancreatic bicarbonate secretion, it failed to alter duodenal mucosal bicarbonate output in either the proximal or the distal duodenum. Glucagon (1 to 8 micrograms/kg-h intravenously) did not affect proximal duodenal mucosal bicarbonate output. It is concluded that VIP, but neither secretin nor glucagon, significantly stimulates human duodenal mucosal bicarbonate secretion.
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PMID:The effect of vasoactive intestinal peptide, secretin, and glucagon on human duodenal bicarbonate secretion. 292 30

Functional and specific receptors for vasoactive intestinal peptide (VIP) (determined by their capacity to bind 125I-VIP and activate adenylate cyclase) and cyclic AMP-dependent phosphodiesterase activities were characterized in enterocytes of human fetal small intestine between 18 and 23 weeks of gestation. Half-maximal stimulation of the cyclase and inhibition of 125I-VIP binding in membrane preparations were respectively observed at 1.4 and 5 X 10(-10) M VIP. The peptides structurally related to VIP activated the cyclic AMP generating system at pharmacological doses (10(-7) M and above) in the following order of potency: VIP greater than PHI greater than GRF greater than secretin. Other peptides or test substances, including GIP, pancreatic glucagon, somatostatin-14, gastrin, CCK, neurotensin, pancreatic polypeptide, PYY, substance P, histamine and isoproterenol are inactive in this system, while the ubiquitous adenylate cyclase activators NaF, forskolin and prostaglandins were effective. These results, combined with the appearance of intestinal VIP in nerve fibers at 8 weeks and with the morphological and enzymatic maturation at 9-12 weeks of the intestinal mucosa, indicate that this neuropeptide may regulate either the differentiation or function of enterocytes during the early development of human intestinal mucosa.
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PMID:Vasoactive intestinal peptide receptor activity in human fetal enterocytes. 298 18

To characterize the molecular components of the vasoactive intestinal peptide (VIP) receptor in human intestine, [125I]VIP was covalently bound to human colonic epithelial membranes using dithio-bis(succinimidyl propionate). Sodium dodecyl sulfate-polyacrylamide gel autoradiographic studies of affinity labeled membranes revealed three major bands corresponding to [125I]VIP-protein complexes of 66,000, 33,000, and 16,000 mol wt. Labeling of the 66,000 and 33,000 mol wt complexes was specific, since it was abolished by VIP, while labeling of the 16,000 mol wt complex was not. Densitometric scanning of autoradiographs indicated that labeling of the 66,000 mol wt complex was inhibited by low VIP concentrations in the 10(-10)-10(-8) M range, but was unaffected by glucagon or octa-cholecystokinin. It was also reduced by VIP-(2-28), with a potency 1/100th that of VIP, and by GTP in the concentration range of 10(-7)-10(-3) M. The 33,000 mol wt complex behaved similarly to the 66,000 mol wt complex with respect to specificity and GTP sensitivity, but differed in one major feature, its affinity for VIP. Its labeling was inhibited by native VIP concentrations in the 10(-9)-10(-7) M range. Assuming one molecule of [125I]VIP bound per molecule of protein, two proteins of 63,000 and 30,000 mol wt were identified as VIP-binding sites. The 63,000 mol wt protein had the properties expected for the VIP receptor coupled to adenylate cyclase in human colon, while the 30,000 mol wt protein was a low affinity binding site. Treatment of human colonic membranes with the sulfhydryl reducing agent dithiothreitol before [125I]VIP binding strongly reduced the labeling of the two proteins. This finding does not support the hypothesis that the low affinity 30,000 mol wt binding site may be a monomer of the high affinity binding site.
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PMID:The human vasoactive intestinal peptide receptor: molecular identification by covalent cross-linking in colonic epithelium. 298 95


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