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)

Growth hormone-releasing factor (GRF), a linear peptide that exists in a number of different molecular forms (GRF-44, -40, -37, and-31) has been shown to be responsible for the acromegaly associated with certain endocrine tumors of the pancreas and other foregut-derived structures. With the use of two anti-sera (#1A850 and G59/901) directed against different segments of the GRF molecule, a series of 24 pancreatic and 35 gastrointestinal endocrine tumors, not associated with acromegaly, were surveyed systematically for immunocytochemical localization of GRF in the tumor cells. Strong immunoreactivity for GRF was encountered in 10 tumors (6 pancreatic and 4 gastrointestinal). While all ten tumors were immunoreactive against G59/901, which recognizes GRF-44, -40, and -37, two jejunal carcinoids showed additional immunostaining with 1A850 that is specific for GRF-44. Seven of these ten tumors were also immunoreactive for a variety of other regulatory peptides and neurotransmitters, including gastrin, insulin, glucagon, serotonin, substance P, somatostatin, pancreatic polypeptide, vasoactive intestinal peptide (VIP), and adrenocorticotropic hormone (ACTH). No consistent pattern of association between GRF and the other regulatory substances was evident. These findings indicate that, even in the absence of associated acromegaly, up to 17% of endocrine tumors of the gastro-entero-pancreatic (GEP) axis show immunoreactivity for GRF and that such reactivity is associated more frequently with pancreatic (25%) than with gastrointestinal (11%) endocrine tumors.
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PMID:Immunocytochemical demonstration of growth hormone-releasing factor in gastrointestinal and pancreatic endocrine tumors. 300 Jan 64

A method is described for preparing human lung parenchymal membranes essentially free of carbon contamination. Using this technique, a high-affinity 125I-VIP-binding site has been characterised. The receptor density is approx. 200 fmol/mg protein, and the Kd of 125I-VIP by saturation binding is 200 pM. The dissociation kinetics are complex and cannot be described by first-order kinetics. Several VIP-related peptides displace 125I-VIP from this binding site with a rank order of potency: VIP greater than rat GRF greater than PHM greater than PHI greater than human GRF greater than secretin greater than glucagon. Displacement curves of these peptides exhibited slope factors significantly less than unity with the exception of human GRF.
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PMID:Characterisation of a high-affinity VIP receptor in human lung parenchyma. 300 15

A 54 year old woman suffered from acromegaly due to a pancreatic islet cell tumour producing GHRH. The tumour was demonstrated on CT scan. The diagnosis was established from elevated plasma levels of GHRH, GH and prolactin, and by the lack of signs of a pituitary adenoma in trans-sphenoidal surgery. Acromegaly was cured by tumour removal. Light microscopically, the tumour showed a medullary and microlobular pattern. The cells were large and often cuspidal. Small granules were found in semi-thin sections. Small aggregations of amyloid fibres were seen, mostly around capillaries. Immunocytochemistry revealed GHRH, NSE, neurotensin, serotonin, VIP and PP. S 100 was positive only in nerve fibres. Staining for GH, ACTH, calcitonin, alpha-HCG, beta-HCG, insulin, glucagon, gastrin, substance P, bombesin and somatostatin was negative. Ultrastructure showed oval partly lobulated nuclei with small nucleoli, moderate amounts of rough endoplasmic reticulum, many free ribosomes, some large Golgi fields and small numbers of secretory granules measuring 150 nm or, in a few cells, 650 nm. Only 4 other cases of pancreatic endocrine tumours causing acromegaly by ectopic GHRH secretion are described in the literature and these were similar to our case in many respects.
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PMID:Morphology of a GHRH producing pancreatic islet cell tumour causing acromegaly. 301 79

Three separate sets of receptors sensitive to VIP, GIP and pancreatic/entero-glucagons, have been characterized in HGT-1 cells. The order of relative potencies of VIP receptor agonists was VIP greater than rh GRF-43, rh GRF-29 greater than PHI greater than hp GRF-40, secretin. G-37 was about 4 times less potent than G-29 in HGT-1 cells (G-29 greater than G-37), whereas it was about 20 times more potent than G-29 in rat fundic glands (G-37 greater than G-29). Adenylate cyclase in HGT-1 cells was stimulated by VIP, G-29, G-37 and GIP, over a concentration from 3.16 X 10(-9) to 3.16 X 10(-7) M GIP. The experimental data: (1) support the enterogastrone activity of GIP, via adenylate cyclase activation and somatostatin release by gastric D cells; (2) demonstrate that HGT-1 cells originating from a human fundic tumor are sensitive to the glucagon-like peptides G-29 and -37, as rat fundic glands; (3) indicate that the pharmacological properties of the VIP receptor in this human gastric cell line are similar to those characterized in normal human gastric glands.
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PMID:Functional receptors for VIP, GIP, glucagon-29 and -37 in the HGT-1 human gastric cancer cell line. 301 90

The structural requirements for VIP interaction with receptors on synaptosomes from rat cerebral cortex was investigated by the ability of VIP and VIP fragments, secretin analogues and fragments, peptides of the VIP/secretin family and several other regulatory peptides to inhibit specific 125I-VIP binding. Only large VIP fragments interacted with the VIP receptors with potencies relative to VIP ranging from 0.9-0.006%. The rank order of inhibition was: VIP 7-27 greater than VIP 11-28 greater than VIP 1-22-NH2 greater than VIP 16-28. Shorter fragments: VIP 18-28; VIP 18-28-NH2; VIP 19-28; VIP 21-28; VIP 22-28; VIP 1-18; VIP 1-18-NH2; VIP 1-10-NH2; VIP 1-6; VIP 16-20 and VIP 16-19 had no effect. Secretin fragments and analogues inhibited 125I-VIP binding with potencies of 2.2-0.01% relative to VIP in the order; secretin greater than (Ala4, Val5) secretin greater than (D-Ala4) secretin greater than (D-Phe6) secretin greater than secretin 5-27 greater than secretin 14-27. Other peptides of the VIP/secretin family inhibited 125I-VIP binding with potencies of 200-1%; avian VIP greater than porcine VIP greater than PHI = secretin greater than human GRF, whereas glucagon and GIP showed no inhibition. Among twenty-five other regulatory peptides only avian PP and somatostatin were inhibitors with relative potencies of 0.02% and 0.03%, respectively. In conclusion it may be emphasized that the intact VIP molecule is essential for VIP interaction with its receptors in the rat brain cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:VIP binding sites on synaptosomes from rat cerebral cortex: structure-binding relationship. 301 96

Vasoactive intestinal peptide (VIP) receptors have been identified in CNS by their chemical specificity and molecular size. Using synaptosomes isolated from rat cerebral cortex, it was shown that central VIP receptors discriminated among natural and synthetic VIP-related peptides, because half-maximal inhibition of [125I]VIP binding to synaptosomes was obtained for 0.6 nM VIP, 9 nM peptide histidine isoleucineamide (PHI), 50 nM VIP 2-28, 70 nM secretin, 100 nM rat growth hormone-releasing factor (GRF), and 350 nM human GRF. Other peptides of the VIP family, such as glucagon and gastric inhibitory polypeptide, did not interact with cortical VIP receptors. The molecular components of VIP receptors in rat cerebral cortex were identified after [125I]VIP cross-linking to synaptosomes using the cross-linker dithiobis(succinimidyl propionate). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of synaptosomal proteins revealed two major [125I]VIP-protein complexes of Mr 49,000 and 18,000. The labeling of the Mr 49,000 component was specific, because it was abolished by native VIP, whereas the labeling of the Mr 18,000 component was not. Natural VIP agonists reduced the labeling of the Mr 49,000 component with the following order of potency: VIP greater than PHI greater than secretin approximately equal to rat GRF. In contrast, glucagon and octapeptide of cholecystokinin were without effect, a result indicating its peptide specificity. Densitometric scanning of autoradiographs showed that the labeling of the Mr 49,000 component was inhibited by low VIP concentrations between 10(-10) and 10(-6) M (IC50 = 0.8 nM), a result indicating the component's high affinity for VIP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular characteristics and peptide specificity of vasoactive intestinal peptide receptors from rat cerebral cortex. 302 Jan 75

Growth hormone-releasing factor (GRF) stimulates the release of growth hormone from the anterior pituitary and is related to the peptides of the glucagon/secretin family. Although the mechanism of action of this hormone has been studied in considerable detail, little is known concerning the GRF receptor itself. We have attempted to label the GRF receptor by chemically coupling the 125I-GRF analog [His1, Nle27]-hGRF(1-32)-NH2 (GRFa) (where Nle is norleucine) to plated rat anterior pituitary cells with the protein cross-linker disuccinimidyl suberate (DSS) (0.1 mM). Verification of biological activity of the 125I-GRFa was confirmed prior to the cross-linking experiments using the reverse hemolytic plaque assay. Whole cell extracts prepared from the cross-linked cells were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography of the dried gels. Four bands of 72, 50, 30, and 26 kDa were detected in autoradiograms from cells exposed to the labeled analog for 20 min (22 degrees C) followed by exposure to DSS for 2 min. The 72-kDa band was interpreted to be bovine serum albumin, which was used as a carrier in initial studies. The 50- and 30-kDa bands were very faint and probably represent nonspecific binding sites since they were unchanged in the presence of excess unlabeled GRFa. The 26-kDa band was diminished in a concentration-dependent manner by unlabeled rat GRF, GRFa, and to a lesser extent by vasoactive intestinal peptide (VIP). It is unlikely, however, that GRFa was acting at a VIP receptor since the labeled analog did not induce prolactin secretion (VIP is a prolactin secretagogue). GRFa also increased cellular cAMP to levels similar to GRF and greater than VIP. Autoradiographs from gels run under nonreducing conditions revealed the 26-kDa band as the major species, indicating that, if a polymeric form of this binding protein exists, it does not involve disulfide linkages. Thus, the best candidate for the putative GRF receptor is the 26-kDa band. We have further demonstrated that the higher concentrations of DSS used previously (5 mM) result in diffuse autoradiograms with multiple bands, suggesting that caution should be exercised when interpreting cross-linking data under these conditions.
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PMID:Cross-linking of a growth hormone releasing factor-binding protein in anterior pituitary cells. 302 63

We have compared the effects of the secretin family of peptides and their synthetic fragments on gastric emptying (GE) and small intestinal transit (SIT) using an unanesthetized rat model which simultaneously measures the GE and SIT of both solids and liquids. The meal consisting of 5% polyethylene glycol w/v, 5% Indian ink v/v and 20 non-digestible plastic beads was given intragastrically 10 minutes after the intraperitoneal injection of 0.5 ml of saline or peptides (2 and 5 micrograms/kg). Plasma secretin and the immunospecificity of secretin fragments were determined. In control rats, the t1/2 for the GE of both solids and liquids were 56 +/- 3.8 and 19 +/- 2.3 minutes, respectively. Liquids emptied faster than the solids and liquids travelled ahead of the solids in the intestine. Secretin (5 micrograms/kg) inhibited GE of both solids and liquids by 33-37%. Secretin delayed the SIT of the meal by approximately 35%. Fragments of secretin and of VIP had no effect on GE and SIT of both solids and liquids. The whole molecule of secretin was required to inhibit GE and to delay SIT of solids and liquids. Glucagon, PHI and growth hormone releasing factor (GHRF1-44) inhibited GE and SIT of both solids and liquids. For all peptides tested, the inhibition of SIT was proportional to the inhibition of GE suggesting that the prolongation of SIT was secondary to delayed GE. These observations indicate that the peptides of the secretin family inhibit GE and prolong SIT. Thus, the structural requirement required for the secretin family of peptides to effect their motor actions on the stomach is similar to that required for pancreatic enzyme secretion.
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PMID:Effect of the secretin family of peptides on gastric emptying and small intestinal transit in rats. 304 99

The glucagon superfamily includes the polypeptides glucagon, secretin, vasoactive inhibitory peptide (VIP), gastric inhibitory peptide and growth hormone-releasing factor (GHRF). Complementary DNA clones which encode the precursors to glucagon, VIP and GHRF have been isolated. Although the sizes and sequences of preproglucagon, prepro VIP and preproGHRF are distinct, the structural organization of the three precursors is similar. Each has a signal peptide, an NH2-terminal peptide and one, two or three peptides whose sequences are related to glucagon. Prepro VIP and preproGHRF also have a COOH-terminal peptide. The sequences of two different anglerfish preproglucagon molecules have been determined and they contain the sequences of glucagon and a related peptide. In contrast, hamster, cow and rat preproglucagon contain the sequences of glucagon and two related peptides. Human and rat prepro VIP contain the sequences of VIP and the related peptide PHM/PHI-27. Human and rat preproGHRF contain the sequence of only one peptide related to glucagon, i.e., GHRF. The genes for both preproglucagon and preproGHRF have been isolated. Their exon-intron organization indicates that each exon encodes a functionally distinct region of the precursor and mRNA.
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PMID:The glucagon superfamily: precursor structure and gene organization. 309 95

Previous research on the favorable effects of mild conformational restriction in the N-terminal region of glucagon has led us to carry out analogue studies on the sequence-related 1-12 region of GRF(1-29)NH2. Replacement of each of the first 11 amino acids by its D-isomer in turn gave a total of 5 analogues exhibiting increases in potency. Other analogues containing multiple D-amino acid replacements were also examined and found to be highly potent, for instance: D-Tyr-1,D-Ala-2, 2630; His-1,D-Ala-2, 3440; Ac-His-1,D-Ala-2, 1574; D-Ala-2,Nle-27, 1840; D-Ala-2,D-Asn-8,Nle-27, 1580; D-Ala-2,D-Asp-3,D-Asn-8,Nle-27, 2000; D-Asp-3,D-Asn-8,Nle-27, 3810 (GRF(1-29) = 100%). It is possible that these results with D-isomers reflect the presence of reverse turns (beta-bends) in this region of GRF. Indeed, the qualitative predictive method of Chou and Fasman supports this theory and indicates reverse turns in the 1-5 and 6-10 sequences. Further studies were performed to test this hypothesis by introducing even more rigidity into the N-terminal region via disulfide bond formation between positions normally containing aromatic amino acids. None of the bridged peptides displayed biological activity which suggests that chain folding does not produce any proximity among N-terminal residues. We had shown previously that position 2(Ala) was extremely sensitive to both conformational and side-chain alterations. This observation was extended to analogues containing Sar and Pro, both of which were also inactive on GH release at the doses tested.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Strategies in the design of synthetic agonists and antagonists of growth hormone releasing factor. 309 97


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