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)

The conformation of several naturally occurring peptide hormones and bioactive oligopeptides in phospholipid solutions was studied by circular dichroism. Phosphatidylcholine induced a partial helix in human gastrin I at neutral pH, but phosphatidylserine did not unless the five consecutive glutamic acid residues in gastrin were protonated. Reduced somatostatin with two lysines and substance P with one arginine and one lysine were partially helical in phosphatidylserine, but not phosphatidylcholine, solution. Both lipids induced a helical conformation in glucagon and its COOH-terminal fragment (19-29) probably because the helical segment is primarily located at the uncharged COOH terminus. Thus, polypeptides with a helix-forming potential can have the helical conformation only when the peptides carry no charge or charges opposite to those on the polar head of the lipid. Renin substrate, which has potentials for the beta form and beta turn, seemed to form a mixture of the two conformations in phosphatidylserine solution. Angiotensin I with a strong probability for the beta form adopted the beta form in phosphatidylserine solution and sleep peptide with no structure-forming potential remained unordered in lipid solutions. The helix usually predominated over the beta form in lipid solutions if the peptide has potentials for both conformations. This could account for the preponderance of helices in bacteriorhodopsin of the purple membrane, which according to its amino acid sequence would have favored the beta form.
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PMID:Lipid-induced ordered conformation of some peptide hormones and bioactive oligopeptides: predominance of helix over beta form. 618 2

To investigate the role of the leader peptide in modulating secretion from living cells, we injected a synthetic peptide into Xenopus oocytes. The peptide consisted of the NH2-terminal leader sequence of mouse immunoglobulin light chain precursor. We found that the leader peptide has two different roles in regulating secretion from the oocytes. First, it competitively inhibits the synthesis of secretory and membrane proteins but not of cytoplasmic proteins. The inhibition occurs both with oocyte proteins and with proteins directed by coinjected myeloma mRNA. The inhibition reaches a maximum 2 hr after injection and decays within 3 hr. It appears to be mediated through the cell membrane, because 125I-labeled leader peptide segregates into the membrane fraction of microinjected oocytes simultaneously with the interference with methionine incorporation. A second role of the microinjected leader peptide is to induce a rapid acceleration in the rate of export of secretory proteins from the oocyte. The maximal enhancement effect is obtained upon injection of 50 ng of leader peptide per oocyte. It is not merely due to the small size, negative charge, or hydrophobicity of the peptide, because enhanced secretion does not occur when glucagon, poly-L-glutamic acid, or Triton X-100 is injected. Furthermore, immunoreaction of the peptide with specific antibodies prior to microinjection prevents the accelerated export. Our observations indicate that in Xenopus oocytes, the leader peptide is involved in both translocation and later step(s) in the secretory pathway.
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PMID:Synthetic leader peptide modulates secretion of proteins from microinjected Xenopus oocytes. 658 Jun 39

PHI--a new candidate hormone from porcine intestinal tract-- corresponds to a linear heptacosapeptide amide of remarkable sequence homology to the known members of the glucagon family, particularly to the vasoactive intestinal peptide (VIP) and secretin. The position 24 usually occupied by an aminodicarboxylic acid omega-amide, in the present case, however, carries a glutamic acid, thus opening the question of whether this structural feature is related to desamidation in one of the isolation and characterization steps or of whether it is significant for this peptide factor. Consequently the heptacosapeptide amides corresponding to the proposed primary structure and to its 24-glutamine analogue have been synthesized. Comparative chromatographic and biological studies on the natural and the two synthetic products have confirmed the correctness of the primary structure proposed for the isolated PHI. Since [24-glutamic acid] and [24-glutamine]PHI exhibit no significant differences in their biological potencies, the main question is still open of whether the position 24 in native PHI is occupied by the aminodicarboxylic acid omega-amide (glutamine) or by N-substituted derivatives (N-glycosyl).
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PMID:Synthesis of the porcine intestinal peptide PHI and its 24-glutamine analogue. 668 13

The Brockmann body of the teleost fish, the tilapia (Oreochromis nilotica) has been considered as a potential source of islet xenograft tissue for patients with insulin-dependent diabetes. This study describes the purification from an extract of tilapia Brockmann bodies of insulin and several peptides arising from different pathways of post-translational processing of two proglucagons, two prosomatostatins and proPYY. The primary structure of tilapia insulin is similar to insulins from other teleosts (particularly the anglerfish, Lophius americanus) except that the strongly conserved glutamine residue at position 5 in the A-chain, a residue that is important in the binding of insulin to its receptor, is replaced by glutamic acid. In common with other teleosts, the tilapia Brockmann body expresses two non-allelic glucagon genes. Alternative pathways of post-translational processing lead to glucagons with 29 and 36 amino acid residues derived from proglucagon I and glucagons with 29 and 32 residues derived from proglucagon II. Glucagon-like peptides with 30 and 34 residues derived from proglucagon II were also isolated. In each case, the longer peptide is a C-terminally extended form of the shorter. Tilapia peptide tyrosine-tyrosine (PYY) was isolated in a C-terminally alpha-amidated from with 36 amino acid residues that is structurally similar (89% sequence identity) to anglerfish PYY. A 30-amino acid peptide, representing the C-terminal flanking peptide of PYY, was also isolated that shows only 53% sequence identity with the corresponding anglerfish peptide. Tilapia somatostatin-14 is identical to mammalian somatostatin but the [Tyr7, Gly10] somatostatin-containing peptide derived from prosomatostatin II contains the additional substitution (Phe11-->Leu) compared with the corresponding peptide from other teleosts.
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PMID:Characterization of the pancreatic hormones from the Brockmann body of the tilapia: implications for islet xenograft studies. 765 83

The effect of L-glutamate was studied on glucagon secretion from rat isolated pancreas perfused with 2.8 mM glucose. L-Glutamate (3.10(-5)-10(-4)M) induced an immediate, transient and concentration-dependent glucagon release. The three non-N-methyl-D-aspartate (NMDA) receptor agonists, kainate (3.10(-5)-3.10(-3)M), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (3.10(-5)-10(-4)M) and quisqualate (3.10(-6)-10(-5)M), all elicited a peak-shaped glucagon response. Compared to glutamate, AMPA and quisqualate exhibited a similar efficacy, whereas kainate caused a 4-fold higher maximal glucagon response. In contrast, NMDA (10(-3)M) was ineffective. The selective antagonist of non-NMDA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 5.10(-5)M), totally prevented the glucagon response to 10(-4) M glutamate (IC50 congruent to 0.8 +/- 0.3 10(-6)M) and 3.10(-4)M kainate. Furthermore, quisqualate at a maximal effective concentration (3.10(-4)M) inhibited the response to kainate (10(-3)M). This study showed that L-glutamate stimulates glucagon release in rat pancreas by activating a receptor of the AMPA subtype.
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PMID:Glutamate stimulates glucagon secretion via an excitatory amino acid receptor of the AMPA subtype in rat pancreas. 768 69

Glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) and its own receptor have been found in the hypothalamus and brain stem of the rat. In an attempt to gain further insight into the role of this peptide in brain functioning we investigated the effects of GLP-1 (7-36)amide on the release of excitatory amino acid neurotransmitters by the ventromedial hypothalamus using an experimental microdialysis approach. GLP-1(7-36)amide produced an immediate increase in the extracellular concentrations of aspartic acid and glutamine, p < 0.01 and p < 0.05, respectively. By contrast, extracellular concentrations of glutamic acid, alanine, threonine, and tyrosine were unaffected. The results of this study show a stimulatory effect of GLP-1(7-36)amide on the release of aspartic acid and glutamine by the ventromedial hypothalamus of the rat.
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PMID:Glucagon-like peptide-1(7-36)amide induces the release of aspartic acid and glutamine by the ventromedial hypothalamus of the conscious rat. 866 66

Aging is an etiologic factor in non-insulin-dependent diabetes mellitus. While the effect of aging on insulin secretion has been described by several classic studies, the characterization of the molecular basis of beta-cell abnormalities is still under way. We recently demonstrated in rats that aging is associated not only with a reduction in insulin secretion but also with diminished levels of intracellular insulin content and the mRNA for insulin. In this study, we investigated whether the molecular abnormalities previously described in the rat beta cell were also present in the mouse (C57BL/6J). Total cellular RNA was isolated from individual pancreata of 3-, 9-, and 30-month-old mice (n = 6 per age group). Samples were subjected to slot-blot analysis by using homologous probes for insulin, glucagon, somatostatin, glucose transporter-2 (glut-2), glucokinase, elastase-I, and beta-actin. We observed a progressive age-dependent decrease in insulin mRNA levels: insulin mRNA levels decreased by 40% with age (p = .007). This paralleled decreases in glut-2 (p = .001) mRNA levels, but it was in contrast with glucokinase mRNA levels which increased markedly (p = .0003). Somatostatin mRNA levels were unchanged, glucagon mRNA levels decreased modesty (p = .01), and mRNA levels for elastase-I and beta-actin increased with age (p = .0001 for either one). In summary, it appears that in the mouse a progressive decline in the activity of the endocrine pancreas occurs with aging. This phenomenon seems to affect only the beta cells and not the alpha or delta cells of the islet of Langerhans or the exocrine pancreas. This progressive decline may represent the biological features of the age-dependent risk for the development of diabetes.
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PMID:Molecular investigation of age-related changes in mouse endocrine pancreas. 880 81

Pancreatic beta-cells are more sensitive to several toxins (e.g., streptozotocin, alloxan, cytokines) than the other three endocrine cell types in the islets of Langerhans. Cytokine-induced free radicals in beta-cells may be involved in beta-cell-specific destruction in type 1 diabetes. To investigate if this sensitivity represents an acquired trait during beta-cell maturation, we used two in vitro cultured cell systems: 1) a pluripotent glucagon-positive pre-beta-cell phenotype (NHI-glu) that, after in vivo passage, matures into an insulin-producing beta-cell phenotype (NHI-ins) and 2) a glucagonoma cell-type (AN-glu) that, after stable transfection with pancreatic duodenal homeobox factor-1 (PDX-1), acquires the ability to produce insulin (AN-ins). After exposure to interleukin (IL)-1beta, both of the insulin-producing phenotypes were significantly more susceptible to toxic effects than their glucagon-producing counterparts. Nitric oxide (NO) production was induced in both NHI phenotypes, and inhibition with 0.5 mmol/l N(G)-monomethyl-L-arginine (NMMA) fully protected the cells. In addition, maturation into the NHI-ins phenotype was associated with an acquired dose-dependent sensitivity to the toxic effect of streptozotocin. Our results support the hypothesis that the exquisite sensitivity of beta-cells to IL-1beta and streptozotocin is an acquired trait during beta-cell maturation. These two cell systems will be useful tools for identification of molecular mechanisms involved in beta-cell maturation and sensitivity to toxins in relation to type 1 diabetes.
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PMID:Beta-cell maturation leads to in vitro sensitivity to cytotoxins. 1058 Apr 20

Over the past decade, numerous studies have been targeted at defining structure-activity relationships of glucagon. Recently, we have found that glucagon(1-29) is hydrolyzed by dipeptidyl peptidase IV (DPIV) to produce glucagon(3-29) and glucagon(5-29); in human serum, [pyroglutamyl (pGlu)(3)]glucagon(3-29) is formed from glucagon(3-29), and this prevents further hydrolysis of glucagon by DPIV (H.-U. Demuth, K. Glund, U. Heiser, J. Pospisilik, S. Hinke, T. Hoffmann, F. Rosche, D. Schlenzig, M. Wermann, C. McIntosh, and R. Pederson, manuscript in preparation). In the current study, the biological activity of these peptides was examined in vitro. The amino-terminally truncated peptides all behaved as partial agonists in cyclic AMP stimulation assays, with Chinese hamster ovary K1 cells overexpressing the human glucagon receptor (potency: glucagon(1-29) > [pGlu(3)]glu- cagon(3-29) > glucagon(3-29) > glucagon(5-29) > [Glu(9)]glu- cagon(2-29)). In competition binding experiments, [pGlu(3)]glucagon(3-29) and glucagon(5-29) both demonstrated 5-fold lower affinity for the receptor than glucagon(1-29), whereas glucagon(3-29) exhibited 18-fold lower affinity. Of the peptides tested, only glucagon(5-29) showed antagonist activity, and this was weak compared with the classical glucagon antagonist, [Glu(9)]glucagon(2-29). Hence, DPIV hydrolysis of glucagon yields low affinity agonists of the glucagon receptor. As a corollary to evidence indicating that DPIV degrades glucagon (Demuth, et al., manuscript in preparation), DPIV-resistant analogs were synthesized. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry was used to assess DPIV resistance, and it allowed kinetic analysis of degradation. Of several analogs generated, only [D-Ser(2)] and [Gly(2)]glucagon retained high affinity binding and biological potency, similar to native glucagon in vitro. [D-Ser(2)]Glucagon exhibited enhanced hyperglycemic activity in a bioassay, whereas [Gly(2)]glucagon was not completely resistant to DPIV degradation.
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PMID:Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon. Characterization of glucagon degradation products and DPIV-resistant analogs. 1066 May 33

The pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor belongs to the glucagon/secretin/vasoactive intestinal polypeptide (VIP) receptor family. We mutated and deleted an amino acid residue (E261) which is located within the second intracellular loop of the rat PACAP type I receptor and which is highly conserved among the receptor family. The wild-type receptor and the mutant receptors were efficiently expressed at the surface of COS-7 cells at nearly the same level and revealed the same high affinity for the agonist PACAP-27. The cAMP contents of COS cells transfected with the E261A, E261Q, and the deletion mutant receptor were 4.6-, 5.7-, and 6.7-fold higher as compared with COS cells transfected with the wild-type receptor. Thus, all the mutant PACAP receptors were constitutively active. The data suggest that the glutamic acid in the second intracellular loop of the PACAP receptor may be a key residue to constrain the receptor in the inactive conformation with respect to its coupling to G(s) proteins.
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PMID:A mutation in the second intracellular loop of the pituitary adenylate cyclase activating polypeptide type I receptor confers constitutive receptor activation. 1071 59


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